Cyclic derivatives as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of MCP-1 of formula (I):  
                 
or pharmaceutically acceptable salt forms thereof, useful for the prevention of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Divisional of U.S. Ser. No. 10/706,448 filed onNov. 12, 2003, which is a Divisional of U.S. Ser. No. 10/027,644 filedon Dec. 20, 2001 which claims priority to U.S. Provisional ApplicationSer. No. 60/256,904 filed Dec. 20, 2000, the entirety of which isincorporated herein by reference.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases, allergic and autoimmune diseases, and in particular, asthma,rheumatoid arthritis, atherosclerosis, and multiple sclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998,338, 436-445 and Rollins, Blood 1997, 90, 909-928). There are two majorclasses of chemokines, CXC and CC, depending on whether the first twocysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1 and −2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72,415-425, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994,91, 2752-2756, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster,New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power, et al., J. Biol. Chem. 1995, 270,19495-19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or“CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1β] (Sanson, et al.,Biochemistry 1996, 35, 3362-3367); CCR-6 (or “CKR-6” or “CC-CKR-6”)[LARC] (Baba, et al., J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or“CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62,634-644); CCR-8 (or “CKR-8” or “CC-CKR-8”) [I-309, TARC, MIP-1](Napolitano et al., J. Immunol., 1996, 157, 2759-2763, and Bernardini,et al., Eur. J. Immunol. 1998, 28, 582-588); CCR-10 (or “CKR-10” or“CC-CKR-10”) [MCP-1, MCP-3] (Bonini, et al., DNA and Cell Biol. 1997,16, 1249-1256); and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickert, etal., J. Biol. Chem. 2000, 275, 90550).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin.Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

The chemokines and their cognate receptors have been implicated as beingimportant mediators of inflammatory, infectious, and immunoregulatorydisorders and diseases, including asthma and allergic diseases, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis (reviewed in: Bharat K. Trivedi, et al, Ann. ReportsMed. Chem. 2000, 35, 191; John Saunders and Christine M. Tarby, DrugDisc. Today 1999, 4, 80; Brett A. Premack and Thomas J. Schall, NatureMedicine 1996, 2, 1174). For example, the chemokine monocytechemoattractant-1 (MCP-1) and its receptor CC Chemokine Receptor 2(CCR-2) play a pivotal role in attracting leukocytes to sites ofinflammation and in subsequently activating these cells. When thechemokine MCP-1 binds to CCR-2, it induces a rapid increase inintracellular calcium concentration, increased expression of cellularadhesion molecules, cellular degranulation, and the promotion ofleukocyte migration. Demonstration of the importance of the MCP-1/CCR-2interaction has been provided by experiments with genetically modifiedmice. MCP-1−/− mice had normal numbers of leukocytes and macrophages,but were unable to recruit monocytes into sites of inflammation afterseveral different types of immune challenge (Bao Lu, et al., J. Exp.Med. 1998, 187, 601). Likewise, CCR-2−/− mice were unable to recruitmonocytes or produce interferon-γ when challenged with various exogenousagents; moreover, the leukocytes of CCR-2 null mice did not migrate inresponse to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100,2552), thereby demonstrating the specificity of the MCP-1/CCR-2interaction. Two other groups have independently reported equivalentresults with different strains of CCR-2−/− mice (William A. Kuziel, etal., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, etal., J. Exp. Med. 1997, 186, 1757). The viability and generally normalhealth of the MCP-1−/− and CCR-2−/− animals is noteworthy, in thatdisruption of the MCP-1/CCR-2 interaction does not induce physiologicalcrisis. Taken together, these data lead one to the conclusion thatmolecules that block the actions of MCP-1 would be useful in treating anumber of inflammatory and autoimmune disorders. This hypothesis has nowbeen validated in a number of different animal disease models, asdescribed below.

Several studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating rheumatoidarthritis. A DNA vaccine encoding MCP-1 was shown recently to amelioratechronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al.,J. Clin. Invest. 2000, 106, 361). Likewise, inflammatory diseasesymptoms could be controlled via direct administration of antibodies forMCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J.Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis(Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps mostsignificantly, a peptide antagonist of MCP-1, MCP-1(9-76), was shownboth to prevent disease onset and to reduce disease symptoms (dependingon the time of administration) in the MRL-1pr mouse model of arthritis(Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).

Three key studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating atherosclerosis.For example, when MCP-1−/− mice are mated with LDL receptor-deficientmice, an 83% reduction in aortic lipid deposition was observed (Long Gu,et al., Mol. Cell 1998, 2, 275). Similarly, when MCP-1 was geneticallyablated from mice which already overexpressed human apolipoprotein B,the resulting mice were protected from atherosclerotic lesion formationrelative to the MCP-1+/+ apoB control mice (Jennifa Gosling, et al., J.Clin. Invest. 1999, 103, 773). Likewise, when CCR-2−/− mice are crossedwith apolipoprotein E mice, a significant decrease in the incidence ofatherosclerotic lesions was observed (Landin Boring, et al, Nature 1998,394, 894).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR-2 interaction in treating multiplesclerosis; all of these studies have been demonstrated in experimentalautoimmune encephalomyelitis (EAE), the standard animal model formultiple scelerosis. Administration of antibodies for MCP-1 to animalswith EAE significantly diminished disease relapse (K. J. Kennedy, etal., J. Neuroimmunol. 1998, 92, 98). Furthermore, two recent reportshave now shown that CCR-2−/− mice are resistant to EAE (Brian T. Fife,et al., J. Exp. Med. 2000, 192, 899; Leonid Izikson, et al., J. Exp.Med. 2000, 192, 1075).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating asthma.Sequestration of MCP-1 with a neutralizing antibody inovalbumin-challenged mice resulted in marked decrease in bronchialhyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J.Exp. Med. 1998, 188, 157). It proved possible to reduce allergic airwayinflammation in Schistosoma mansoni egg-challenged mice through theadministration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J.Immunol. 1997, 158, 4398). Consistent with this, MCP-1−/− mice displayeda reduced response to challenge with Schistosoma mansoni egg (Bao Lu, etal., J. Exp. Med. 1998, 187, 601).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating kidney disease.Administration of antibodies for MCP-1 in a murine model ofglomerularnephritis resulted in a marked decrease in glomerular crescentformation and deposition of type I collagen (Clare M. Lloyd, et al., J.Exp. Med. 1997, 185, 1371). In addition, MCP-1−/− mice with inducednephrotoxic serum nephritis showed significantly less tubular damagethan their MCP-1+/+ counterparts (Gregory H. Tesch, et al., J. Clin.Invest. 1999, 103, 73).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating systemic lupus erythematosus.Crossing of MCP-1−/− mice with MRL-FAS^(lpr) mice—the latter of whichhave a fatal autoimmune disease that is analogous to human systemiclupus erythematosus—results mice that have less disease and longersurvival than the wildtype MRL-FAS^(lpr) mice (Gregory H. Tesch, et al.,J. Exp. Med. 1999, 190, 1813).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating colitis. CCR-2−/− mice wereprotected from the effects of dextran sodium sulfate-induced colitis(Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating alveolitis. When rats with IgAimmune complex lung injury were treated intravenously with antibodiesraised against rat MCP-1 (JE), the symptoms of alveolitis were partiallyaleviated (Michael L. Jones, et al., J. Immunol. 1992, 149, 2147).

Other studies have provided evidence that MCP-1 is overexpressed invarious disease states not mentioned above. These reports provide strongcorrelative evidence that MCP-1 antagonists could be useful therapeuticsfor such diseases. Two reports described the overexpression of MCP-1 inthe intestinal epithelial cells and bowel mucosa of patients withinflammatory bowel disease (H. C. Reinecker, et al., Gastroenterology1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc. Biol. 1996, 59,804). Two reports describe the overexpression of MCP-1 rats with inducedbrain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, andJoan W. Berman, et al., J. Immunol. 1996, 156, 3017). Another study hasdemonstrated the overexpression of MCP-1 in rodent cardiac allografts,suggesting a role for MCP-1 in the pathogenesis of transplantarteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad. Sci. USA1993, 90, 6086). The overexpression of MCP-1 has been noted in the lungendothelial cells of patients with idiopathic pulmonary fibrosis (HarryN. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371).Similarly, the overexpression of MCP-1 has been noted in the skin frompatients with psoriasis (M. Deleuran, et al., J. Dermatol. Sci. 1996,13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127).Finally, a recent report has shown that MCP-1 is overexpressed in thebrains and cerebrospinal fluid of patients with HIV-1-associateddementia (Alfredo Garzino-Demo, WO 99/46991).

It should also be noted that CCR-2 has been implicated as a co-receptorfor some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). Ithas also been determined that the use of CCR-2 as an HIV co-receptor canbe correlated with disease progression (Ruth I. Connor, et al., J. Exp.Med. 1997, 185, 621). This finding is consistent with the recent findingthat the presence of a CCR-2 mutant, CCR2-64I, is positively correlatedwith delayed onset of HIV in the human population (Michael W. Smith, etal., Science 1997, 277, 959). Although MCP-1 has not been implicated inthese processes, it may be that MCP-1 antagonists that act via bindingto CCR-2 may have beneficial therapeutic effects in delaying the diseaseprogression to AIDS in HIV-infected patients.

Recently, a number of groups have described the development of smallmolecule antagonists of MCP-1 (reviewed in: Bharat K. Trivedi, et al,Ann. Reports Med. Chem. 2000, 35, 191). Workers at Teijen and Combichemreported the use of cyclic amines (A) as MCP-1 (Tatsuki Shiota, et al.,WO 99/25686; Tatsuki Shiota, et al., WO 00/69815) and MIP-1α (ChristineTarby and Wilna Moree, WO 00/69820) antagonists. These compounds aredistinguished from those of the present invention (I) by the requirementfor the central cyclic amine grouping.

A number of other groups have also described the development of smallmolecule antagonists of the MCP-1/CCR-2 interaction. To date,indolopiperidines (Ian T. Forbes, et al., Bioorg. Med. Chem. Lett. 2000,10, 1803), spiropiperidines (Tara Mirzadegan, et al., J. Biol. Chem.2000, 275, 25562), quaternary amines (Masanori Baba, et al., Proc. Natl.Acad. Sci. 1999, 96, 5698), 2-substituted indoles (Alan Faull and JasonKettle, WO 00/46196; Andrew John Barker, et al., WO 99/07351; AndrewJohn Barker, et al., WO 99/07678), pyrazolone derivatives (JanakKhimchand Padia, et al., U.S. Pat. No. 6,011,052, 2000), 2-substitutedbenzimidazoles (David Thomas Connor, et al., WO 98/06703),N,N-dialkylhomopiperazines (T. Shiota, et al., WO 97/44329), bicyclicpyrroles (Andrew J. Barker, et al., WO 99/40913 and Andrew J. Barker, etal., WO 99/40914), and 5-aryl pentadienamides (K. G. Carson, et al.,Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA,1999) have all been reported as MCP-1 antagonists. The foregoingreference compounds are readily distinguished structurally from thepresent invention by virtue of substantial differences in the terminalfunctionality, the attachment functionality, or the core functionality.The prior art does not disclose nor suggest the unique combination ofstructural fragments that embody in the novel compounds describedherein. Furthermore, the prior art does not disclose or suggest that thecompounds of the present invention would be antagonists of MCP-1.

It should be noted that CCR-2 is also the receptor for the chemokinesMCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338,436-445). Since it is presumed that the new compounds of formula (I)described herein antagonize MCP-1 by binding to the CCR-2 receptor, itmay be that these compounds of formula (I) are also effectiveantagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that aremediated by CCR-2. Accordingly, when reference is made herein to“antagonism of MCP-1,” it is to be assumed that this is equivalent to“antagonism of chemokine stimulation of CCR-2.”

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel antagonists or partialagonists/antagonists of MCP-1 receptor activity, or pharmaceuticallyacceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating rheumatoidarthritis, multiple sclerosis, and atherosclerosis, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides novel cyclic derivatives for use intherapy.

The present invention provides the use of novel cyclic derivatives forthe manufacture of a medicament for the treatment of inflammatorydiseases.

These and other features of the invention, which will become apparentduring the following detailed description, have been achieved by theinventors' discovery that compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinZ, m, n, s, R¹, R^(1a), R^(1b), R², R⁸, R⁹, R¹⁰, R^(10a), R¹¹, R¹², andR¹³ are defined below, are effective modulators of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novelcompounds of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

-   ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the    cycloalkyl group is saturated or partially unsaturated; or a    heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or    partially unsaturated, the heterocycle containing a heteroatom    selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the    heterocycle optionally containing a —C(O)—; ring B being substituted    with 0-2 R⁵;-   Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and    —SO₂NH—;-   R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl,    C₁₋₄ cycloalkyl, CF₃, or alternatively, R^(1a) and R^(1b) are taken    together to from ═O;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,    (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),    (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),    (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆    haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e),    C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted    with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-4 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(4e), and a    (CHR)_(r)-4-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);-   R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4d), at each occurrence, is selected from methyl, CF₃, C₁₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j),    —C(O)NR^(4h)R^(4h), —OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h),    —NR^(4h)C(O)OR^(4j), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R^(4h), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀    carbocyclic;-   R^(4i), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue;-   R^(4j), at each occurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue;-   R⁵, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C (O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),    (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),    C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-3 R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(5c);-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(5e);-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),    (CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(=NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(5e);-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2    R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl; R^(5g) is independently selected from —C(O)R^(5b),    —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(5e);-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O) (CR′R′)_(r)R^(6b),    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),    (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(6e);-   alternatively, two R⁶ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(6a), at each occurrence, is selected from H, methyl substituted    with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈    alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with    0-2 R^(6e), a (CH₂)_(r)-C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(6e);-   R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2    R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), a    (CH₂)_(r)-C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d),    —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)    (CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a), (CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),    (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e);-   alternatively, two R⁷ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(7a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),    C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted    with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈    alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2    R^(7e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),    —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(6e);-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R⁹ is selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and (CH₂)—R¹;-   R¹⁰ and R^(10a) are independently selected from H, and C₁₋₄alkyl    substituted with 0-1 R^(10b),-   alternatively, R¹⁰ and R^(10a) can join to form a C₃₋₆ cycloalkyl;-   R^(10b), at each occurrence, is independently selected from —OH,    —SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),    (CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b),    (CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(11e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),    (CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),    (CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(12e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹³, at each occurrence, is independently selected from methyl, C₂₋₄    alkyl substituted with 0-1 R^(13b);-   R^(13b) is selected from —OH, —SH, —NR^(13c)R^(13c),    —C(O)NR^(13c)R^(13c), and —NHC(O) R^(13c);-   R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   n is selected from 1 and 2;-   m is selected from 0 and 1;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1, 2, 3, and    4;-   r, at each occurrence, is independently selected from 0, 1, 2, 3,    and 4;-   s, at each occurrence, is independently selected from 0 and 1; and-   t, at each occurrence, is independently selected from 2, 3, and 4.

[2] Thus, in a another embodiment, the present invention provides novelcompounds of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

-   ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the    cycloalkyl group is saturated or partially unsaturated; or a    heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or    partially unsaturated, the heterocycle containing a heteroatom    selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the    heterocycle optionally containing a —C(O)—; ring B being substituted    with 0-2 R⁵;-   Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and    —SO₂NH—;-   R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl,    C₁₋₄ cycloalkyl, CF₃, or alternatively, R^(1a) and R^(1b) are taken    together to from ═O;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁶;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁷;-   R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,    (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d),    (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),    (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆    haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-3 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e),    C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted    with 0-3 R^(4e), and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-4 R^(4e);-   R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(4e);-   R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4d), at each occurrence, is selected from methyl, CF₃, C₁₋₆ alkyl    substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3    R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4i),    —C(O)NR^(4h)R^(4h), —OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h),    —NR^(4h)C(O)OR^(4i), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, and phenyl;-   R^(4h), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀    carbocyclic;-   R^(4i), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue;-   R^(4i), at each occurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue;-   R⁵, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O) OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b),    (CRR)_(r)S(O)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),    C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-3 R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(5c);-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-3 R^(5e);-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(5e);-   R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,    (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH,    (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f),    (CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl,    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and    (CH₂)_(r)phenyl substituted with 0-3 R^(5e);-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2    R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀    carbocyclic residue substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(5e);-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)    (CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a),    (CR′R′)_(r)C(O)NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b),    (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b),    (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a),    (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(6e);-   alternatively, two R⁶ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(6a), at each occurrence, is selected from H, methyl substituted    with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈    alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with    0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with    0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(6e);-   R^(6b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2    R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(6e);-   R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2    R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), a    (CH₂)_(r)-C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d),    —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b),    (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a),    (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b),    (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a),    (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e);-   alternatively, two R⁷ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(7a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e),    C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted    with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(7e);-   R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈    alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(7e);-   R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2    R^(7e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d),    —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted    with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    and (CH₂)_(r)phenyl substituted with R^(6e);-   R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R⁹ is selected from, H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and (CH₂)—R¹;-   R¹⁰ and R^(10a) are independently selected from H, and C₁₋₄alkyl    substituted with 0-1 R^(10b),-   alternatively, R¹⁰ and R^(10a) can join to form a C₃₋₆ cycloalkyl;-   R^(10b), at each occurrence, is independently selected from —OH,    —SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c);-   R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b),    (CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b),    (CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a),    (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(11e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b),    (CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b),    (CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a),    (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue    substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H, C₁₋₄    alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₄    alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic    residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆    carbocyclic residue substituted with 0-3 R^(12e), and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹³, at each occurrence, is independently selected from methyl, C₂₋₄    alkyl substituted with 0-1 R^(13b);-   R^(13b) is selected from —OH, —SH, —NR^(13c)R^(13c),    —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c);-   R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   n is selected from 1 and 2;-   m is selected from 0 and 1;-   p, at each occurrence, is independently selected from 0, 1, and 2;-   q, at each occurrence, is independently selected from 1, 2, 3, and    4;-   r, at each occurrence, is independently selected from 0, 1, 2, 3,    and 4;-   s, at each occurrence, is independently selected from 0 and 1; and-   t, at each occurrence, is independently selected from 2, 3, and 4.

[3] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R¹⁰ and R^(10a) are H;-   m is 0;-   n is 1; and-   s is 0.

[4] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   ring B is selected from    ring B being optionally substituted with 0-1 R⁵ and-   R¹¹ and R¹² are H.

[5] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁵, at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,    (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a),    (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)NR^(5a)C(O)OR^(5d),    (CRR)_(r)OC(O)NR^(5a)R^(5a), (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    CRR(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b),    (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b),    (CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆    haloalkyl;-   R^(5a), at each occurrence, is independently selected from H,    methyl, C₁₋₆ alkyl substituted with 0-2 R^(5e) wherein the alkyl is    selected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl,    hexyl, C₃ alkenyl substituted with 0-1 R^(5e), wherein the alkenyl    is selected from allyl, C₃ alkynyl substituted with 0-1 R^(5e)    wherein the alkynyl is selected from propynyl, and a (CH₂)_(r)—C₃₋₄    carbocyclic residue substituted with 0-5 R^(5e), wherein the    carbocyclic residue is selected from cyclopropyl, and cyclobutyl;-   R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(5e), wherein the alkyl is selected from methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, a    (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with 0-2 R^(5e),    wherein the carbocyclic residue is selected from cyclopropyl, and    cyclobutyl; and-   R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl    substituted with 0-2 R^(5e), wherein the alkyl is selected from    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl,    C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue    substituted with 0-3 R^(5e).

[6] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl,    (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d),    (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b),    (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b),    (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b);-   R, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with R^(6e);-   R⁵, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl,    (CH₂)_(r)OH, (CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a),    (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a),    (CH₂)_(r)NR^(5a)C(O)OR^(5d), (CH₂)_(r)NR^(5a)C (O) R^(5b),    (CH₂)_(r)C(O) OR^(5b), (CH₂)_(r)OC(O)R^(5b),    (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl;-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl,    cyclopropyl, and cyclobutyl; and-   r, at each occurrence, is selected from 0, 1, and 2.

[7] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R¹ is selected from phenyl substituted with 0-2 R⁶, and a 5-10    membered heteroaryl system containing 1-4 heteroatoms selected from    N, O, and S, substituted with 0-3 R⁶ wherein the heteroaryl is    selected from benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,    benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,    furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl,    isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl.-   R² is selected from phenyl substituted with 0-2 R⁷, and a 5-10    membered heteroaryl system containing 1-4 heteroatoms selected from    N, O, and S, substituted with 0-3 R⁷ wherein the heteroaryl is    selected from benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,    benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,    furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl,    isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl.-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(s)SH,    (CRR)_(s)OR^(4d), (CRR)_(s)SR^(4d), (CRR)_(s)NR^(4a)R^(4a),    (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),    (CRR)_(s)NR^(4a)C(O)R^(4b), (CRR)_(s)OC(O)NR^(4a)R^(4a),    (CRR)_(s)NR^(4a)C(O)OR^(4d), (CRR)_(s)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(s)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b);-   R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl;-   R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl; and-   R⁸ and R⁹ are independently selected from methyl, ethyl, propyl,    i-propyl, and cyclopropyl.

[8] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)OH, (CRR)_(r)O(CRR)_(r)R^(6d),    (CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(6d),    (CRR)_(r)C(O)OH, (CRR)_(r)C(O)(CRR)_(r)R^(6b),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)NR^(6f)C(O)(CRR)_(r)R^(6b),    (CRR)_(r)C(O)O(CRR)_(r)R^(6d), (CRR)_(r)NR^(6a)C(O)NR^(6a)R^(6a),    (CRR)_(r)NR^(6a)C(S)NR^(6a)R^(6a), (CRR)_(r)OC(O)(CRR)_(r)R^(6b),    (CRR)_(r)S(O)_(p)(CRR)_(r)R^(6b), (CRR)_(r)S(O)₂NR^(6a)R^(6a),    (CRR)_(r)NR^(6f)S(O)₂(CRR)_(r)R^(6b),    (CRR)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a), C₁₋₆ haloalkyl, and    (CRR)_(r)phenyl substituted with 0-3 R^(6e);-   R^(6a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,    hexyl, cyclopropyl and phenyl;-   R^(6b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and    phenyl;-   R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s- butyl, t-butyl, pentyl, hexyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CRR)_(r)NR^(7a)R^(7a), (CRR)_(r)OH,    (CRR)_(r)O(CH)_(r)R^(7d), (CRR)_(r)SH, (CRR)_(r)C(O)H,    (CRR)_(r)S(CRR)_(r)R^(7d), (CRR)_(r)C(O)OH,    (CRR)_(r)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)NR^(7a)R^(7a),    (CRR)_(r)NR^(7f)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)O(CRR)_(r)R^(7d),    (CRR)_(r)OC(O)(CRR)_(r)R^(7b), (CRR)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CRR)_(r)NR^(7a)C(O)O(CRR)_(r)R^(7d),    (CRR)_(r)S(O)_(p)(CRR)_(r)R^(7b), (CRR)_(r)S(O)₂NR^(7a)R^(7a),    (CRR)_(r)NR^(7f)S(O)₂(CRR)_(r)R^(7b), C₁₋₆ haloalkyl, and    (CRR)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, CH₂cyclopropyl, and benzyl;-   R^(7b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,    cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃,    pyrrolidinyl, morpholinyl, and azetidinyl;-   R^(7d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and    cyclopropyl;-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl; and-   r is 0 or 1.

[9] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂, NR^(7a)R^(7a),    NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, OCF₃,    C(O)R^(7b), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),

[10] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   ring B is selected from-   Z is —C(O)—;-   R^(1a) and R^(1b) are selected from H and methyl, or alternatively,    R^(1a) and R^(1b) are taken together to form ═O;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶    wherein the aryl group is selected from phenyl and naphthyl, and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N and O, substituted with 0-3 R⁶ wherein the heteroaryl system    is selected from furyl, indolyl, and benzotriazolyl;-   R² is phenyl substituted with 0-1 R⁷;-   R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    I-butyl, t-butyl, pentyl, hexyl, and (CH₂)_(r)C(O) R^(4b);-   R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl,    Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H, SR^(6d), NR^(6a)R^(6a),    OC(O)R^(6b), S(O)_(p)R^(6b), (CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃;-   R^(6a) is H methyl, or ethyl;-   R^(6b) is H or methyl;-   R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl;-   R⁹ is selected from H, methyl, and (CH₂)—R¹; and-   r is 0 or 1.

[11] In another embodiment, the present invention provides novelcompounds of formula (I), wherein the compound is selected from

-   N-[2-[[(1S,2S)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide,-   N-[2-[[(1S,2S)-2-[[(2,4,6-Trimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(4-Benzyloxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2,4-Difluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2-Chloro-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2-Trifluoromethyl-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2,4-Dichlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2-Fluoro-6-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(2-Chloro-5-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[(2,4-Dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-2-[(4-Chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;

-   N-[2-[[(cis)-2-[[(4-Nitrophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(4-Isopropylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(4-Trifluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(4-Trifluoromethoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(4-Phenoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(2-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(3-Indolyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[1-(4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[Bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[(4-Chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[(4-(Methylthio)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[(4-(Methylsulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[(4-Iodobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[(4-(Aminosulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Methylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Fluorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[Benzoylamino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Bromobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Phenoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Trifluoromethylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(5-Benzotriazolecarbonyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Iodobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Cyanobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Trifluoromethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Formylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Carbomethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Nitrobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Methoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Methylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Methylsulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Aminosulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Isopropylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Phenylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-(N,N-diethylsulfamoyl)benzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[(4-Trifluoromethylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodobenzamide;-   2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-chlorobenzamide;-   N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-chlorobenzamide;-   N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-trifluoromethoxybenzamide;-   Tert-butyl    2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;-   2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide    trifluoroacetate;-   4-(Aminosulfonyl)-N-((cis)-2-{[({[2-(trifluoromethyl)anilino]carbonyl}amino)acetyl]amino}cyclohexyl)benzamide;-   4-(Aminosulfonyl)-N-{(cis)-2-[({[(3-chlorophenyl)sulfonyl]amino)acetyl)amino]cyclohexyl}benzamide;-   Ethyl    2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;-   Methyl    2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;-   Tert-butyl    N-Methyl-2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;-   Ethyl    2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;-   2-(Benzylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-bromo    benzamide;-   Tert-butyl    2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethoxy)phenylcarbamate;-   2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethoxy    benzamide;-   2-(Allylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide,-   2-(cyclopropylmethylene)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(butyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((2-methyl-2-propyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(acetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethyl    benzamide;-   2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethyl    benzamide;-   2-(Trifluoroacetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethyl    benzamide;-   2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-nitro    benzamide;-   Iso-propyl    2-[([2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl)amino)carbonyl]-4-(iodo)phenylcarbamate;-   Tert butyl    2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;-   2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3,5-dinitro    benzamide;-   2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Cyclopentylmethylenecarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Methylsulfonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((2-Methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Ethylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino)-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl    benzamide;-   2-{[1-Pyrrolidinylcarbonyl]amino}-N-2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino)tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide;-   1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;-   [2-({[5-benzyloxycarbonylamino-2-(4-methylthiobenzoylamino)cyclohexylcarbamoyl]-methyl}carbamoyl)-4-trifluoromethylphenyl]carbamic    acid tert-butyl ester;-   {4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;-   {4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamic    acid benzyl ester;-   1-(4-Methanesulfonylbenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl-4-aminocyclohexane;-   1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)cyclohexane;-   1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(3-methylureido)cyclohexane;-   1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-aminocyclohexane;-   1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-(2-propylamino)cyclohexane;-   1-(4-Methylthio-benzoylamino)-2-[2-(2-Amino-5-trifluoromethyl-benzoylamino)-acetylamino]-4-aminocyclohexane;-   4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)-cyclohexane;-   1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-5-aminocyclohexane;-   2-Amino-N-({2-[(4-methylthiophenylamino)methyl]cyclohexylcarbamoyl}-methyl)-5-(trifluoromethyl)benzamide;-   2-Isopropylamino-N-{[(cis)2-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl)-5-trifluoromethylbenzamide;-   2-(3-Isopropylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl)-5-trifluoromethylbenzamide;-   2-(3-Morpholinylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl)-5-trifluoromethylbenzamide;-   2-Amino-N-({2-(cis)-[3-(4-methylthiophenyl)ureido]cyclohexylcarbamoyl}methyl)-5-trifluoromethyl    benzamide;-   (2-[({2-(Cis)-[3-(4-methanesulfonylphenyl)ureido]cyclohexylcarbamoyl)methyl)carbamoyl]-4-trifluoromethylphenyl}carbamic    acid tert-butyl ester;-   2-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide;-   2-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino)-1-methyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   2-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino)-1-propyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide;-   2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;-   N-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;-   N-{[4-Dimethylamino-2-(4-methylsulfanyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide    trifluoroacetate;-   N-{[2-(4-Chloro-benzylamino)-4-dimethylamino-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide    trifluoroacetate;-   N-{[4-Dimethylamino-2-(4-methoxy-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide    trifluoroacetate; and-   N-{[4-Dimethylamino-2-(4-methyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide    trifluoroacetate.

In another embodiment, the present invention is directed to apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity that ismediated by the CCR2 receptor comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofFormula (I), said disorders being selected from osteoarthritis,aneurism, fever, cardiovascular effects, Crohn's disease, congestiveheart failure, autoimmune diseases, HIV-infection, HIV-associateddementia, psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, of Formula (I), wherein said disordersbeing selected from psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, of Formula (I), wherein said disordersbeing selected from alveolitis, colitis, systemic lupus erythematosus,nephrotoxic serum nephritis, glomerularnephritis, asthma, multiplesclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, of Formula (I), wherein said disordersbeing selected from asthma, multiple sclerosis, artherosclerosis, andrheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing rheumatoid arthritis, comprising administering toa patient in need thereof a therapeutically effective amount of acompound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating or preventing multiple sclerosis, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

In another embodiment, the present invention is directed to a method fortreating or preventing atherosclerosis, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula(I).

In another embodiment, the present invention is directed to a method fortreating or preventing asthma, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating or preventing inflammatory diseases, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of CCR2 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, ring B is selected from

ring B being optionally substituted with 0-1 R⁵.

-   In another embodiment, ring B is selected from-   In another embodiment, Z is —C(O)—.-   In another embodiment, R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈    alkenyl, C₃₋₈ alkynyl, (CRR)_(q)OH, (CHR)_(s)SH, (CRR)_(t)OR^(4d),    (CHR)_(t)SR^(4d), (CHR)_(t)NR^(4a)R^(4a), (CHR)_(q)C(O)OH,    (CHR)_(r)C(O)R^(4b), (CHR)_(r)C(O)NR^(4a)R^(4a),    (CHR)_(t)NR^(4a)C(O)R^(4b), (CHR)_(t)OC(O)NR^(4a)R^(4a),    (CHR)_(t)NR^(4a)C(O)OR^(4d), (CHR)_(t)NR^(4a)C(O)R^(4b),    (CHR)_(r)C(O)OR^(4b), (CHR)_(t)OC(o)R^(4b), (CHR)_(r)S(O)_(p)R^(4b),    (CHR)_(r)S(O)₂NR^(4a)R^(4a), (CHR)_(r)NR^(4a)S(O)₂R^(4b); and-   R, at each occurrence, is independently selected from H, methyl,    ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and    (CH₂)_(r)phenyl substituted with R^(6e).-   In another embodiment, R⁴ is selected from H, methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(t)SH,    (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a),    (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a),    (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b),    (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b),    (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b).-   R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl; and-   R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl, pentyl, and cyclopropyl.-   In another embodiment, R⁴ is selected from H, methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)C(O)R^(4b).-   In another embodiment, R⁵, at each occurrence, is independently    selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    allyl, propynyl, (CH₂)_(r)OH, (CH₂)_(r)OR^(5d),    (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b),    (CH₂)_(r)C(O)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)R^(5b),    (CH₂)_(r)OC(O)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)OR^(5d),    (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)C(O)OR^(5b),    (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆    haloalkyl; and-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl,    cyclopropyl, and cyclobutyl.-   In another embodiment, R⁵, at each occurrence, is independently    selected from H, (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)R^(5b),    and (CH₂)_(r)NR^(5a)C(O)OR^(5d).-   In another embodiment, R¹ is selected from phenyl substituted with    0-2 R⁶, naphthyl substituted with 0-2 R⁶, and a 5-10 membered    heteroaryl system containing 1-4 heteroatoms selected from N, O, and    S, substituted with 0-3 R⁶ wherein the heteroaryl is selected from    indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,    benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,    furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl,    isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl.-   In another embodiment, R¹ is selected from a C₆₋₁₀ aryl group    substituted with 0-3 R⁶ wherein the aryl group is selected from    phenyl and naphthyl, and a 5-10 membered heteroaryl system    containing 1-4 heteroatoms selected from N and O, substituted with    0-3 R⁶ wherein the heteroaryl system is selected from furyl,    indolyl, and benzotriazolyl.-   In another embodiment, R² is selected from phenyl substituted with    0-2 R⁷, and a 5-10 membered heteroaryl system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R⁷    wherein the heteroaryl is selected from benzimidazolyl,    benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,    benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,    benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,    indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,    pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,    pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and    tetrazolyl.-   In another embodiment, R² is selected from phenyl substituted with    0-2 R⁷.-   In another embodiment, R⁶, at each occurrence, is selected from C₁₋₈    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br,    I, F, NO₂, CN, (CH₂)_(r)NR^(6a)R^(6a), (CH₂)_(r)OH,    (CH₂)_(r)O(CH₂)_(r)R^(6d), (CH₂)_(r)SH, (CH₂)_(r)C(O)H,    (CH₂)_(r)S(CH₂)_(r)R^(6d), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)(CH₂)_(r)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a),    (CH₂)_(r)NR^(6f)C(O)(CH₂)_(r)R^(6b), (CH₂)_(r)C(O)O(CH₂)_(r)R^(6d),    (CH₂)_(r)OC(O)(CH₂)_(r)R^(6b), (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(6b),    (CH₂)_(r)S(O)₂NR^(6a)R^(6a), (CH₂)_(r)NR^(6f)S(O)₂(CH₂)_(r)R^(6b),    (CH₂)_(r)NR^(6f)S(O)₂ NR^(6a)R^(6a), C₁₋₆ haloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(6e);-   R^(6a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,    hexyl, cyclopropyl and phenyl;-   R^(6b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and    phenyl;-   R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl;-   R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; and-   R^(6f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl.-   In another embodiment, R⁶ is selected from methyl, ethyl, propyl,    i-propyl, butyl, F, Cl, Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H,    SR^(6d), NR^(6a)R^(6a), OC(O)R^(6b), S(O)_(p)R^(6b),    (CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃;-   R^(6a) is H, methyl, or ethyl;-   R^(6b) is H or methyl; and-   R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl.-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s- butyl, t-butyl, pentyl, hexyl,    (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CH₂)_(r)NR^(7a)R^(7a), (CH₂)_(r)OH, (CH₂)_(r)O(CH)_(r)R^(7d),    (CH₂)_(r)SH, (CH₂)_(r)C(O)H, (CH₂)_(r)S(CH₂)_(r)R^(7d),    (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)(CH₂)_(r)R^(7b),    (CH₂)_(r)C(O)NR^(7a)R^(7a), (CH₂)_(r)NR^(7f)C(O)(CH₂)_(r)R^(7b),    (CH₂)_(r)C(O)O(CH₂)_(r)R^(7d), (CH₂)_(r)OC(O)(CH₂)_(r)R^(7b),    (CH₂)_(r)NR^(7a)C(O) NR^(7a)R^(7a),    (CH₂)_(r)NR^(7a)C(O)O(CH₂)_(r)R^(7d),    (CH₂)_(r)S(O)_(p)(CH₂)_(r)R^(7b), (CH₂)_(r)S(O)₂NR^(7a)R^(7a),    (CH₂)_(r)NR^(7f)S(O)₂(CH₂)_(r)R^(7b), C₁₋₆ haloalkyl, and    (CH₂)_(r)phenyl substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and    cyclopropyl;-   R^(7b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;-   R^(7d), at each occurrence, is selected from methyl, CF₃, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and    cyclopropyl;-   R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; and-   R^(7f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,    cyclopropyl, and phenyl.-   In another embodiment, R⁷ is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂,    NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b),    NR^(7a)C(O)OR^(7d), CF₃, OCF₃, C(O)R^(7b), NR^(7f)C(O)NHR^(7a), and    NHS(O)₂R^(7b).-   In another embodiment, R⁸ is H.-   In another embodiment, R⁹ is H, methyl, or CH₂—R¹.-   In another embodiment, R¹¹ and R¹² are H.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment todescribe additional even more preferred embodiments of the presentinvention. Furthermore, any elements of an embodiment are meant to becombined with any and all other elements from any of the embodiments todescribe additional embodiments.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl”, isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heterotams independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, examples of heteroaryls are indolyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or in combination with otheractive ingredients effective to inhibit MCP-1 or effective to treat orprevent inflammatory disorders.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

A series of compounds of formulas 6 and 7 are available via the methodsshown in Scheme 1. A cyclic diamine 1 can be monoprotected to provide 2.This material can be coupled to the acid 3 to yield the amide 4. Oncethe protecting group is removed, a reductive amination can be performedto afford target 6. This can be alkylated again to give target 7.

A series of compounds of formulas 10 and 11 are available as shown inScheme 2. The protecting group on intermediate 4 can be removed, and areductive amination can be performed to yield 8. This material can becoupled to acid 9 to give target 10. A second target can be synthesizedby protecting group removal from intermediate 4 and direct coupling of 9to give the target 11.

A series of compounds of formulas 20 and 21 are synthesized as shown inScheme 3. A cyclic 1,2-diamine like 12 (for example, the commerciallyavailable 1,2-diaminocyclohexane) can be mono-protected as a Boccarbamate via BOC-ON (Brechbiel et al., Bioorg. Med. Chem . 1997, 5,1925). The amine 13 can be directly coupled with 14 to yield the amide15. In a second pathway, or a stepwise version, 13 can be coupled to 16as the first step. The resulting amide 17 can be deprotected (N-Cbz),and then coupled to 9a to form the same 15. The N-Boc of 15 can beremoved to give the key intermediate amine 19. One target can besynthesized via a reductive amination with 5 to yield 20. The secondtarget can be synthesized by performing another reductive amination togive 21.

A series of compounds of formulas 23 and 24 can be synthesized as shownin Scheme 4. The key intermediate 19 can be alkyated via reductiveamination to give 22. The first target can be synthesized by coupling 22with 9 to give 23. The second target can be synthesized by directcoupling of 19 with 9 to afford 24.

A series of compounds of formulas 32 and 34 are prepared via the methodsshown in Scheme 5. An amine 25 (for example, the commercially available2-benzyloxycyclopentylamine) can be protected as the carbamate 26 viaBoc₂O. Removal of the benzyl group affords the alcohol 27, which can beconverted to the mesylate 28. The mesylate can be displaced with NaN₃ toprovide the azide 29. This can be reduced to the key intermediate 30.This amine can be coupled with 9 to afford the amide 31. The firsttarget can be synthesized by deprotection with TFA followed by couplingwith 3 to give 32. Another target can be synthesized from 30 by firstperforming a reductive amination to give 33. The amine 33 can be coupledto 9, deprotected with TFA, and coupled with 3 to afford the target 34.

A series of compounds of formulas 39 and 40 are synthesized as shown inScheme 6. The key intermediate 30 can be protected as the Cbz carbamate35 via Cbz₂O. The Boc group can be removed, and the acid 3 can becoupled to provide amide 37. The amide 37 can be deprotected to theamine 38, and a reductive amination can be performed to give the firsttarget 39. The second target can be synthesized via another reductiveamination on 39 to afford 40.

As shown in Schemes 5 and 6, intermediate 30 can be converted intoseveral target molecules. As a key intermediate, 30 can be synthesizedseveral different ways. As shown in Scheme 7, a cyclic olefin 41 [manyare available for this: 1-carbobenzyloxy-1,2,3,6-tetrahydropyridine(D'Andrea et al., J. Org. Chem. 1991, 56, 3133), 4-aminocyclohexenederivatives (Bisagni et al., J. Heterocycl. Chem. 1990, 27, 1801 orPfister et al. Synthesis 1983, 38-40), or 3-pyrroline derivatives (Laiet al., J. Med. Chem. 1997, 40, 226)] can be oxidized to the epoxide 42(Jacobsen et al., J. Org. Chem. 1997, 62, 4197). This can be opened withNaN₃ to give the azide 43, which can be reduced. The resulting amine 44can be protected as the N-Boc 45. This can be converted to the mesylate46 and then the azide 47. In the final step, the azide 47 can be reducedto the key intermediate 30.

A series of compounds of formula 58 are synthesized as shown in Scheme8. The cyclic, unsaturated acid 48 can be converted into the2-aminocyclocarboxylate 51 via two routes. In the first route,esterification followed by a Michael reaction (Davies et al., J. Chem.Soc. Perkin Trans. I, 1994, 1411) gives 50. Simple hydrogenation givesthe 2-aminocyclocarboxylate 51. In the second route, the Michaelreaction (Schneider et al., Chem Ber. 1959, 92, 1594) can be performedwith ammonia to give 51 after esterification. Going forward, a Cbz group(or another appropriate protecting group) can be installed understandard conditions to afford 52. Enolization of the ester with LDA (oranother appropriate base) followed by alkylation gives the substituted53. The ester is then removed to afford the free acid 54. A Curtius(Yamada et al., Tetrahedron 1974, 30, 2151) or Hofmann reaction (Zhanget al., J. Org. Chem. 1997, 62, 6918) can then be performed to give thediamino derivative 55 (as in 35, Scheme 6). After removal of the Bocgroup, the right-side piece 3 can be coupled on to give the amide 57.This can be elaborated as shown in Scheme 3, 4, 5, and 6 to give thedesired target 58.

A series of comounds of formula 64 are synthesized as shown in Scheme 9.In this case, intermediate 52 (or another appropriate protecting groupfor Cbz) from Scheme 8 can be used as a starting point. Enolization ofthe ester with LDA (or another appropriate base) followed by alkylationgives the substituted 59. The ester is then removed to afford the freeacid 60. A Curtius (Yamada et al., Tetrahedron 1974, 30, 2151) orHofmann reaction (Zhang et al., J. Org. Chem. 1997, 62, 6918) can thenbe performed to give the diamino derivative 61 (as in 35, Scheme 6). TheCbz can be removed via hydrogenation to give the free amine 62. Asbefore, this material can be coupled to the right-side piece 3 to givethe amide 63. This can then be elaborated as shown in Scheme 3, 4, 5,and 6 to give the desired target 64.

A series of compounds of formula 74 are synthesized as shown in Scheme10. A cyclic ester acid 65 can be alkylated with LDA (or anotherappropriate base) and the electrophile R¹¹-LG to give 66. This materialcan be esterified via the isourea (Mathias Synthesis 1979, 561) toafford the diester 67. Hydrolysis leads to the acid 68, which canundergo a Curtius or a Hofmann to give 69 (or another appropriateprotecting group for Cbz). Once again, the ester can be alkylated withthe electrophile R¹²-LG to provide 70. The tert-butyl ester can beremoved to the acid 71, and a Curtius or Hofmann reaction provides theamine 72 (much like 35, Scheme 6). As before, 72 can be coupled to theright-side piece 3 to give the amide 73. This can then be elaborated asshown in Scheme 3, 4, 5, and 6 to give the desired target 74.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “g”for gram or grams, “mg” for milligram or milligrams, “mL” for milliliteror milliliters, “¹H” for proton, “h” for hour or hours, “M” for molar,“min” for minute or minutes, “MHz” for megahertz, “MS” for massspectroscopy, “NMR” for nuclear magnetic resonance spectroscopy, “rt”for room temperature, “tlc” for thin layer chromatography, “lv/v” forvolume to volume ratio. “R” and “S” are stereochemical designationsfamiliar to those skilled in the art.

Example 1N-[2-[[(1S,2S)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(1a) N-tert-Butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine (C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (3.0 g) was dissolved in DMFprior to the addition of, 4-methylmorpholine (7.7 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (3.8 g). This solutionwas cooled to 0° C., and BOP (6.8 g) was added in portions. The reactionwas warmed to rt and was stirred overnight. The reaction was quenchedwith water and EtOAc. The EtOAc layer was washed with 1 N HCl solution,NaHCO₃ solution, and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the resulting residue gave theN-Boc derivative[(1S,2S)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid 1,1-dimethylethyl ester (5.0 g). MS found: (M+Na)⁺=466.3.

(1b) The above derivative (1a)(5.0 g) was dissloved in CH₂Cl₂ (10 mL)and cooled to 0° C. Trifluoroacetic acid (10 mL) was added and thereaction was warmed to rt. After 1 h, the solvent was removed to give anoily residue. This was re-dissolved in CH₂Cl₂ and then re-concentratedto the amineN-[2-[[(1S,2S)-2-aminocyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(5.0 g). MS found: (M+H)⁺=344.3.

(1c) The above amine (1b)(110 mg) was dissolved in THF prior to theaddition of Hunigs's base (0.2 mL). Next, 4-chlorobenzaldehyde (30 mg)was added along with 4A molecular sieves. After 3 h, NaHB(OAc)₃ (76 mg)was added. This mixture was stirred an additional 2 h before thereaction was quenched with NaHCO₃ solution. This was extracted withEtOAc. The EtOAc was dried and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title benzamideN-[2-[[(1S,2S)-2-[[(4-chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(30 mg). MS found: (M+H)⁺=468.2.

Example 2N-[2-[[(1S,2S)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(2a) 2,4-Dimethylbenzaldehyde (0.04 mL) was incorporated into the aboveprocedure, (1c), to give the title benzamide (35 mg). MS found:(M+H)⁺=462.3.

Example 3N-[2-[[(1S,2S)-2-[[(2,4,6-Trimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(3a) 2,4,6-trimethylbenzaldehyde (0.07 mL) was incorporated into theabove procedure, (1c), to give the title benzamide (30 mg). MS found:(M+H)⁺=476.4.

Example 4N-[2-[[(1S,2S)-2-[[(4-Benzyloxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(4a) 4-Benzyloxybenzaldehyde (108 mg) was incorporated into the aboveprocedure, (1c), to give the title benzamide (40 mg). MS found:(M+H)⁺=540.4.

Example 5N-[2-[[(1S,2S)-2-[[(2,4-Difluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(5a) 2,4-Difluorobenzaldehyde (0.06 mL) was incorporated into the aboveprocedure, (1c), to give the title benzamide (25 mg). MS found:(M+H)⁺=470.3.

Example 6N-[2-[[(1S,2S)-2-[[(2-Chloro-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(6a) 2-Chloro-4-fluorobenzaldehyde (75 mg) was incorporated into theabove procedure, (1c), to give the title benzamide (15 mg). MS found:(M+H)⁺=486.2.

Example 7N-[2-[[(1S,2S)-2-[[(2-Trifluoromethyl-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(7a) 2-Trifluoromethyl-4-fluorobenzaldehyde (0.06 mL) was incorporatedinto the above procedure, (1c), to give the title benzamide (20 mg). MSfound: (M+H)⁺=520.2.

Example 8N-[2-[[(1S,2S)-2-[[(2,4-Dichlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(8a) 2,4-Dichlorobenzaldehyde (91 mg) was incorporated into the aboveprocedure, (1c), to give the title benzamide (10 mg). MS found:(M+H)⁺=502.1.

Example 9N-[2-[[(1S,2S)-2-[[(2-Fluoro-6-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(9a) 2-Fluoro-6-trifluoromethylbenzaldehyde (0.06 mL) was incorporatedinto the above procedure, (1c), to give the title benzamide (30 mg). MSfound: (M+H)⁺=520.2.

Example 10N-[2-[[(1S,2S)-2-[[(2-Chloro-5-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(10a) 2-Chloro-5-trifluoromethylbenzaldehyde (0.083 mL) was incorporatedinto the above procedure, (1c), to give the title benzamide (20 mg). MSfound: (M+H)⁺=536.2.

Example 11N-[2-[[(1S,2S)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(11a) 1-Naphthaldehyde (0.05 mL) was incorporated into the aboveprocedure, (1c), to give the title benzamide (6 mg). MS found:(M+H)⁺=484.3.

Example 12 N-[2-[[(1S, 2S)-2-[bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(12a) 3-Furaldehyde (0.03 mL) was incorporated into the above procedure,(1c), to give the title benzamide (30 mg). MS found: (M+H)⁺=504.3.

Example 13N-[2-[[(1S,2S)-2-[(2,4-Dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(13a) The title benzamide from Example (2a)(25 mg) was dissolved in THFprior to the addition of Hunigs's base (0.01 mL). Next, 37% formaldehyde(0.02 mL) was added along with 4A molecular sieves. After 3 h,NaHB(OAc)₃ (46 mg) was added. This mixture was stirred an additional 2 hbefore the reaction was quenched with NaHCO₃ solution. This wasextracted with EtOAc. The EtOAc was dried and concentrated. Reversephase HPLC purification (gradient elution, water/acetonitrile/TFA) ofthe resulting residue provided the title benzamideN-[2-[[(1S,2S)-2-[(2,4-dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(10 mg). MS found: (M+H)⁺=476.3.

Example 14N-[2-[[(1S,2S)-2-[(4-Chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(14a) The title benzamide from Example 1 (21 mg) was dissolved in THFprior to the addition of Hunigs's base (0.01 mL). Next, 37% formaldehyde(0.017 mL) was added along with 4A molecular sieves. After 3 h,NaHB(OAc)₃ (38 mg) was added. This mixture was stirred an additional 2 hbefore the reaction was quenched-with NaHCO₃ solution. This wasextracted with EtOAc. The EtOAc was dried and concentrated. Reversephase HPLC purification (gradient elution, water/acetonitrile/TFA) ofthe resulting residue provided the title benzamideN-[2-[[(1S,2S)-2-[(4-chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(10 mg). MS found: (M+H)⁺=482.3.

Example 15N-[2-[[(cis)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(15a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (preparedin an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine see: C. Wu et al.,Bioorg. Med. Chem. 1997, 5, 1925) was substituted into Example 1, step(1a), and 2,4-dimethylbenzaldehyde (0.1 mL) was substituted into step(1c) to give the title benzamideN-[2-[[(cis)-2-[[(2,4-dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(40 mg). MS found: (M+H)⁺=462.4.

Example 16N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(16a) 4-Chlorobenzaldehyde (167 mg) was incorporated into Example 15 togive the title benzamide (30 mg). MS found: (M+H)⁺=468.3.

Example 17N-[2-[[(cis)-2-[[(4-Nitrophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(17a) 4-Nitrobenzaldehyde (67 mg) was incorporated into Example 15 togive the title benzamide (45 mg). MS found: (M+H)⁺=479.3.

Example 18N-[2-[[(cis)-2-[[(4-Isopropylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(18a) 4-Isopropylbenzaldehyde (0.07 mL) was incorporated into Example 15to give the title benzamide (20 mg). MS found: (M+H)⁺=476.3.

Example 19N-[2-[[(cis)-2-[[(4-Trifluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(19a) 4-Trifluorobenzaldehyde (0.05 mL) was incorporated into Example 15to give the title benzamide (40 mg). MS found: (M+H)⁺=502.3.

Example 20N-[2-[[(cis)-2-[[(4-Trifluoromethoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(20a) 4-Trifluoromethoxybenzaldehyde (0.09 mL) was incorporated intoExample 15 to give the title benzamide (50 mg). MS found: (M+H)⁺=518.2.

Example 21N-[2-[[(cis)-2-[[(4-Phenoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(21a) 4-Phenoxybenzaldehyde (0.1 mL) was incorporated into Example 15 togive the title benzamide (40 mg). MS found: (M+H)⁺=526.2.

Example 22N-[2-[[(cis)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(22a) 1-Naphthaldehyde (0.05 mL) was incorporated into Example 15 togive the title benzamide (30 mg). MS found: (M+H)⁺=484.3.

Example 23N-[2-[[(cis)-2-[[(2-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(23a) 2-Naphthaldehyde (53 mg) was incorporated into Example 15 to givethe title benzamide (20 mg). MS found: (M+H)⁺=484.3.

Example 24N-[2-[[(cis)-2-[[(3-Indolyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(24a) Indole-3-carboxaldehyde (65 mg) was incorporated into Example 15to give the title benzamide (10 mg). MS found: (M+H)⁺=473.3.

Example 25N-[2-[[(cis)-2-[[1-(4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(25a) 2′-Chloroacetophenone (0.2 mL) was incorporated into Example 15 togive the title benzamide (20 mg). MS found: (M+H)⁺=482.2.

Example 26N-[2-[[(cis)-2-[Bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(26a) 3-Furaldehyde (0.04 mL) was incorporated into Example 15 to givethe title benzamide (30 mg). MS found: (M+H)⁺=504.3.

Example 27N-[2-[[(1S,2R)-2-[(4-Chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(27a) (1S, 2S)-1-Amino-2-benzyloxycyclopentane (12.1 g) (LancasterSynthesis Inc.) was dissolved in THF prior to the addition of water (58mL) and Et₃N (35.4 mL). After cooling to 0° C., Boc₂O (15.23 g) in THF(58 mL) was added dropwise. The reaction was warmed to rt and wasstirred overnight. The THF was removed and EtOAc was added. Thissolution was washed with 1M HCl and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated to give (1S,2S)-N-(t-butoxycarbonyl)-2-benzyloxycyclopentane (18.4 g). MS found:(M+Na)⁺=314.2.

(27b) The above material (27a) (18.4 g) was dissolved in MeOH (90 mL)prior to the addition of 20% Pd(OH)₂/C. This reaction was placed on theParr apparatus at 60 psi hydrogen pressure. After shaking 4.25 h, thePd/C was filtered and the solution was concentrated (13.4 g). A portionof this material (12.7 g) was dissolved in CH₂Cl₂ prior to the additionof Et₃N (26.5 mL). After cooling to 0° C., MsCl (7.4 mL) was addeddropwise. This continued stirring for 2.5 h, before water was added. TheCH₂Cl₂ layer was also washed with NaHCO₃ solution and brine. The CH₂Cl₂was dried (MgSO₄), filtered, and concentrated. This material wasdissolved in DMF (180 mL) prior to the addition of NaN₃. The resultingsolution was heated at 85° C. for 2 h. After cooling, EtOAc was addedalong with brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated to a solid. This solid was dissolved in MeOH (100 mL) priorto the addition of 10% Pd/C. A hydrogen ballooon was attached, and themixture stirred overnight. The Pd/C was filtered off, and the MeOH wasremoved to give (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine (6 g). MS found:(M+H)⁺=201.4.

(27c) 4-Chlorobenzoic acid (258 mg) was dissolved in DMF (8 mL) prior tothe addition of Hunig's base (1.0 mL). After cooling to 0° C., BOPReagent (729 mg) was added. This was stirred for 15 min before (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b), (300 mg)was added as a DMF solution (2 mL). The resulting mixture warmed to rtand was stirred overnight. EtOAc was added along with 1 N HCl solution.The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. The resultingmaterial was dissolved in CH₂Cl₂ (10 mL) and cooled to 0° C. TFA (1.2mL) was added and the reaction was stirred for 2 h. This solution wasconcentrated prior to the addition of DMF (8 mL). After cooling to 0°C., Hunig's base (1 mL) and [[3-(trifluoromethyl)benzoyl]amino]aceticacid (386 mg) were added. BOP Reagent (655 mg) was added next, and themixture was stirred overnight. EtOAc was added along with 1 N HClsolution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, andbrine. The EtOAc was dried (MgSO4), filtered, and concentrated. This wasstirred in 1:1 EtOAc/hexane and then filtered to give the titlebenzamideN-[2-[[(1S,2R)-2-[(4-chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(310 mg) as a solid. MS found: (M+H)⁺=468.2.

Example 28N-[2-[[(1S,2R)-2-[(4-(Methylthio)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(28a) 4-(Methylthio)benzoic acid (277 mg) was incorporated into Example27, step (27c), to give the title benzamide (320 mg). MS found:(M+H)⁺=480.2.

Example 29N-[2-[[(1S,2R)-2-[(4-(Methylsulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(29a) 4-(Methylsulfonyl)benzoic acid (330 mg) was incorporated intoExample 27, step (27c), to give the title benzamide (209 mg). MS found:(M+H)⁺=512.1.

Example 30N-[2-[[(1S,2R)-2-[(4-Iodobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(30a) 4-Iodobenzoic acid (409 mg) was incorporated into Example 27, step(27c), and HPLC purification (gradient elution, water/acetonitrile/TFA)gave the title benzamide (20 mg). MS found: (M+H)⁺=431.0.

Example 31N-[2-[[(1S,2R)-2-[(4-(Aminosulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(31a) 4-Carboxybenzenesulfonamide (79 mg) was incorporated into Example27, step (27c), and the resulting residue was purified by reverse phaseHPLC purification (gradient elution, water/acetonitrile/TFA) to providedthe title benzamide (140 mg). MS found: (M+Na)⁺=535.1.

Example 32N-[2-[[(1S,2R)-2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(32a) (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b),(1.0 g) was dissolved in THF (5 mL) and water (5 mL) prior to theaddition of Et₃N (2.8 mL). After cooling to 0° C., Cbz₂O (1.6 g) in THFwas added. This mixture was warmed to rt and was stirred overnight. TheTHF was removed and EtOAc was added. The EtOAc layer was washed with 1 NHCl and brine. The EtOAc was dried (MgSO₄), filtered, and concentratedto a white solid (1.7 g). This white solid was dissolved in CH₂Cl₂ (20mL) and cooled to 0° C. TFA (4 mL) was added and the reaction wasstirred for 2 h. This solution was concentrated prior to the addition ofDMF (10 mL). After cooling to 0° C., 4-methylmorpholine (2.2 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (386 mg) were added. BOPReagent (2.5 g) was added, and the mixture was stirred overnight. EtOAcwas added along with 1 N HCl solution. The EtOAc layer was washed with 1N HCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO4),filtered, and concentrated. The resulting residue was purified by flashchromatography to afford the N-Cbz derivative[(1R,2S)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclopentyl]carbamicacid phenylmethyl ester (1.3 g).

(32b) The above derivative (32a) (1.2 g) was dissolved in MeOH (100 mL)prior to the addition of 20% Pd(OH)₂ (240 mg). The solution was placedon a Parr shaker at 55 psi hydrogen pressure overnight. The Pd(OH)₂ wasfiltered off and the solution was concentrated. A portion of theresulting residue (132 mg) was dissolved in THF prior to the addition ofacetic acid (0.23 mL) and 4-chlorobenzaldehyde (85 mg). After 45 min,NaHB(OAc)₃ was added. This mixture was stirred overnight before thesolution was concentrated. EtOAc was added. The EtOAc layer was washedwith NaHCO₃ solution. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamideN-[2-[[(1S,2R)-2-[[(4-chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(63 mg). MS found: (M+H)⁺=454.1.

Example 33N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(33a) 2,4-Dimethylbenzaldehyde (0.1 mL) was incorporated into Example32, step (32b), to give the title benzamide (47 mg). MS found:(M+H)⁺=448.2.

Example 34N-[2-[[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(34a) 4-Methylbenzaldehyde (0.08 mL) was incorporated into Example 32,step (32b), to give the title benzamide (43 mg). MS found: (M+H)⁺=434.1.

Example 35N-[2-[[(cis)-2-[(4-Chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(35a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (preparedin an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (5.0 g) was dissolved in DMF (70mL). After cooling to 0° C., 4-methylmorpholine (7.7 mL) and[[3-(trifluoromethyl)benzoyl]amino]acetic acid (5.8 g) were added. BOPReagent (11.3 g) was added, and the mixture was stirred overnight. EtOAcwas added along with 1 N HCl solution. The EtOAc layer was washed with 1N HCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄),filtered, and concentrated. The resulting residue was purified by flashchromatography to afford the N-Boc derivative[(cis)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid 1,1-dimethylethyl ester (8.5 g). MS found: (M+H)⁺=444.1.

(35b) A portion of the above derivative (35a) (5 g) was dissolved inCH₂Cl₂ (10 mL) and cooled to 0° C. TFA (10 mL) was added and thereaction was stirred for 2 h. This solution was concentrated and aportion (128 mg) was dissolved in DMF (5 mL). After cooling to 0° C.,4-methylmorpholine (0.15 mL) and 4-chlorobenzoic acid (53 mg) wereadded. BOP Reagent (136 mg) was added next, and the mixture was stirredovernight. EtOAc was added along with 1 N HCl solution. The EtOAc layerwas washed with 1 N HCl, NaHCO₃ solution, and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) of the resulting residueprovided the title benzamideN-[2-[[(cis)-2-[(4-chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(30 mg). MS found: (M+H)⁺=482.2.

Example 36N-[2-[[(cis)-2-[(4-Methylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(36a) 4-Methylbenzoic acid (41 mg) was incorporated into Example 35,step (35b), to give the title benzamide (40 mg). MS found:(M+Na)⁺=484.2.

Example 37N-[2-[[(cis)-2-[(4-Fluorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(37a) 4-Fluorobenzoic acid (45 mg) was incorporated into Example 35,step (35b), to give the title benzamide (10 mg). MS found: (M+H)⁺=466.2.

Example 38N-[2-[[(cis)-2-[Benzoylamino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(38a) Benzoic acid (45 mg) was incorporated into Example 35, step (35b),to give the title benzamide (15 mg). MS found: (M+H)⁺=448.2.

Example 39N-[2-[[(cis)-2-[(4-Bromobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(39a) 4-Bromobenzoic acid (58 mg) was incorporated into Example 35, step(35b), to give the title benzamide (18 mg). MS found: (M+H)⁺=528.1.

Example 40N-[2-[[(cis)-2-[(4-Phenoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(40a) 4-Phenoxybenzoic acid (67 mg) was incorporated into Example 35,step (35b), to give the title benzamide (10 mg). MS found: (M+H)⁺=540.2.

Example 41N-[2-[[(cis)-2-[(4-Trifluoromethylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(41a) 4-Trifluorobenzoic acid (67 mg) was incorporated into Example 35,step (35b), to give the title benzamide (38 mg). MS found: (M+H)⁺=516.2.

Example 42N-[2-[[(cis)-2-[(5-Benzotriazolecarbonyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(42a) Benzotriazole-5-carboxylic (45 mg) was incorporated into Example35, step (35b), to give the title benzamide (8 mg). MS found:(M+H)⁺=489.2.

Example 43N-[2-[[(cis)-2-[(4-Iodobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(43a) 4-Iodobenzoic acid (74 mg) was incorporated into Example 35, step(35b), to give the title benzamide (25 mg). MS found: (M+H)⁺=574.2.

Example 44N-[2-[[(cis)-2-[(4-Cyanobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(44a) 4-Cyanobenzoic acid (49 mg) was incorporated into Example 35, step(35b), to give the title benzamide (40 mg). MS found: (M+H)⁺=473.3.

Example 45N-[2-[[(cis)-2-[(4-Trifluoromethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(45a) 4-Trifluoromethoxybenzoic acid (55 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (15 mg). MS found:(M+H)⁺=532.2.

Example 46N-[2-[[(cis)-2-[(4-Formylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(46a) 4-Formylbenzoic acid (36 mg) was incorporated into Example 35,step (35b), to give the title benzamide (10 mg). MS found: (M+H)⁺=476.3.

Example 47N-[2-[[(cis)-2-[(4-Carbomethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(47a) 4-Carbomethoxybenzoic acid (38 mg) was incorporated into Example35, step (35b), to give the title benzamide (55 mg). MS found:(M+H)⁺=506.2.

Example 48N-[2-[[(cis)-2-[(4-Nitrobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(48a) 4-Nitrobenzoic acid (140 mg) was incorporated into Example 35,step (35b), to give the title benzamide (200 mg). MS found:(M+H)⁺=493.2.

Example 49N-[2-[[(cis)-2-[(4-Aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(49a) The above material, Example 48, (10 mg) was dissolved in MeOHprior to the addition of 10% Pd/C. A hydrogen balloon was attached andthe mixture was stirred overnight. The Pd/C was filtered off and theMeOH removed to give the title benzamideN-[2-[[(cis)-2-[(4-aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(5 mg). MS found: (M+H)⁺=463.2.

Example 50N-[2-[[(cis)-2-[(4-Methoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(50a) 4-Methoxybenzoic acid (31 mg) was incorporated into Example 35,step (35b), to give the title benzamide (47 mg). MS found: (M+H)⁺=478.3.

Example 51N-[2-[[(cis)-2-[(4-Methylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(51a) 4-Methylthiobenzoic acid (38 mg) was incorporated into Example 35,step (35b), to give the title benzamide (10 mg). MS found: (M+H)⁺=494.2.

Example 52N-[2-[[(cis)-2-[(4-Methylsulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(52a) 4-Methylsulfonylbenzoic acid (45 mg) was incorporated into Example35, step (35b), to give the title benzamide (40 mg). MS found:(M+H)⁺=526.2.

Example 53N-[2-[[(cis)-2-[(4-Aminosulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(53a) 4-Aminosulfonylbenzoic acid (50 mg) was incorporated into Example35, step (35b), to give the title benzamide (40 mg). MS found:(M+H)⁺=527.2.

Example 54N-[2-[[(cis)-2-[(4-Isopropylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(54a) 4-Isopropylbenzoic acid (45 mg) was incorporated into Example 35,step (35b), to give the title benzamide (30 mg). MS found: (M+H)⁺=490.3.

Example 55N-[2-[[(cis)-2-[(4-Phenylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(55a) 4-Phenylthiobenzoic acid (63 mg) was incorporated into Example 35,step (35b), to give the title benzamide (27 mg). MS found: (M+H)⁺=556.2.

Example 56N-[2-[[(cis)-2-[(4-(N,N-diethylsulfamoyl)benzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(56a) N,N-Diethyl-4-sulfamoylbenzoic acid (63 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (30 mg). MS found:(M+H)⁺=583.3.

Example 57N-[2-[[(cis)-2-[(4-Trifluoromethylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(57a) 4-Trifluoromethylthiobenzoic acid (117 mg) was incorporated intoExample 35, step (35b), to give the title benzamide (20 mg). MS found:(M+H)⁺=548.2.

Example 58N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(58a) 1-(N-(t-butoxycarbonyl))-1,2-(cis)-cyclopropanediamine hydrogenchloride (Langlois et al, Bioorg. Med. Chem. 2000, 8, 321) (850 mg) wasdissolved in DMF (10 mL). After cooling to 0° C., 4-methylmorpholine(2.7 mL) and [[3-(trifluoromethyl)benzoyl]amino]acetic acid (1.4 g) wereadded. BOP Reagent (2.4 g) was added, and the mixture was stirredovernight. EtOAc was added along with 1 N HCl solution. The EtOAc layerwas washed with 1 N HCl, NaHCO₃ solution, and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. The resulting residue was purifiedby flash chromatography to afford the N-Boc derivative[(cis)-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]cyclopropyl]carbamicacid 1,1-dimethylethyl ester (1.5 g). MS found: (M+Na)⁺=424.1.

(58b) The above derivative (58a) (1.2 g) was dissloved in CH₂Cl₂ andcooled to 0° C. Trifluoroacetic acid was added and the reaction waswarmed to rt. After 2 h, the solvent was removed. A portion of theresulting residue (100 mg) was dissolved in THF prior to the addition ofacetic acid (0.014 mL), 4-chlorobenzaldehyde (34 mg), and 4A molecularsieves (100 mg). After 30 min, NaHB(OAc)₃ (76 mg) was added, and themixture was stirred overnight at rt. EtOAc and NaHCO₃ solution wereadded. This was extracted with EtOAc. The EtOAc was dried andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide,N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(10 mg). MS found: (M+H)⁺=550.1.

Example 59N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(59a) 3,4-Dimethylbenzaldehyde (0.03 mL) was incorporated into Example58, step (58b), to give the title benzamide (20 mg). MS found:(M+H)⁺=420.1.

Example 60N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(60a) 4-Methylbenzaldehyde (28 mg) was incorporated into Example 58,step (58b), to give the title benzamide (10 mg). MS found: (M+H)⁺=406.1.

Example 612-Amino-N-[2-[[(cis)-2-[(4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodobenzamide

(61a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (preparedin an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (10.7 g) was dissolved in DMF(167 mL). After cooling to 0° C., diisopropylethylamine (35 mL) andN-Cbz-Gly-OH (12.1 g) were added. HATU Reagent (21.9 g) was added, andthe mixture was stirred for 4 days (out of convenience). EtOAc was addedalong with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl,NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated (14.6 g). The resulting residue was dissloved in CH₂Cl₂ (20mL) prior to the addition of TFA (20 mL). After 15 min, the solution wasconcentrated to a foam. This material was dissolved in DMF (70 mL).After cooling to 0° C., diisopropylethylamine (25 mL) and4-aminosulfonylbenzoic acid (8.7 g) were added. BOP Reagent (19.2 g) wasadded, and the mixture was stirred overnight. EtOAc was added along with1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. CH₂Cl₂ was added and the off-white solid was collected togive benzyl(cis)-2-[(2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethylcarbamate(8.1 g). MS found: (M+H)⁺=511.1.

(61b) The material from above benzyl(cis)-2-[(2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethylcarbamate(217 mg) was dissolved in 30% HBr/AcOH (5 mL) at rt. After 1 h, Et₂O wasadded and the solid was collected to giveN-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide. MS found: (M+H)⁺=355.2.

(61c) The above material, (61b),N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide (59 mg) was dissolved in DMF (1 mL). After cooling to0° C., diisopropylethylamine (0.1 mL) and 2-amino-5-iodobenzoic acid (43mg) were added. BOP Reagent (72 mg) was added, and the mixture wasstirred overnight. EtOAc was added along with NaHCO₃ solution. The EtOAcwas dried (MgSO₄), filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title benzamide2-amino-N-{2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}-5-iodobenzamide(6 mg). MS found: (M+Na)⁺=622.2.

Example 622-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-chlorobenzamide

(62a) 2-Amino-5-chlorobenzoic acid (65 mg) was incorporated into Example61, step (61c), to give the title benzamide (8 mg). MS found:(M+Na)⁺=530.3.

Example 63N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-chlorobenzamide

(63a) 3-Chlorobenzoic acid (43 mg) was incorporated into Example 61,step (61c), to give the title benzamide (50 mg). MS found: (M+H)⁺=515.2.

Example 64N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-trifluoromethoxybenzamide

(64a) 3-Trifluoromethoxybenzoic acid (57 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (47 mg). MS found:(M+H)⁺=543.1.

Example 65 Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate

(65a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (87 mg)(Takagishi et al., Synlett 1992, 360) was incorporated into Example 61,step (61c), to give the title benzamide (150 mg). MS found:(M+Na)⁺=664.3.

Example 662-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamidetrifluoroacetate

(66a) The material from above, (65a), (125 mg) was dissolved in CH₂Cl₂(5 mL) prior to the addition of TFA (5 mL). After 1 h, the solution wasconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of a portion (25 mg) of the resulting residueprovided the title benzamide (10 mg). MS found: (M+Na)⁺=564.2.

Example 674-(Aminosulfonyl)-N-((cis)-2-{[({[2-(trifluoromethyl)anilino]carbonyl)amino)acetyl]amino}cyclohexyl)benzamide

(67a)N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide, (61b), (100 mg) was dissolved in DMF (3 mL) prior tothe addition of 4-methylmorpholine (0.13 mL) and 2-trifluoromethylphenylisocyanate (0.05 mL). After stirring overnight, EtOAc was added and thesolution was washed with 1N HCl. The EtOAc was dried, filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide (50 mg). MS found: (M+Na)⁺=564.3.

Example 684-(Aminosulfonyl)-N-{(cis)-2-[({[(3-chlorophenyl)sulfonyl]amino)acetyl)amino]cyclohexyl}benzamide

(68a)N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamidehydrogen bromide, (61b), (70 mg) was dissolved in DMF (2.5 mL) prior tothe addition of 3-chlorobenzenesulfonyl chloride (51 mg). After stirringovernight, EtOAc was added and the solution was washed with 1N HCl. TheEtOAc was dried, filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the resultingresidue provided the title benzamide (25 mg). MS found: (M+H)⁺=530.1.

Example 69 Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

(69a) 2-(Ethyloxycarbonyl)amino-5-iodobenzoic acid (185 mg) wasincorporated into Example 61, step (61c), to give the titlephenylcarbamate (87 mg). MS found: (M−H)⁻=670.9.

Example 70 Methyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

(70a) 2-(Methyloxycarbonyl)amino-5-iodobenzoic acid (177 mg) wasincorporated into Example 61, step (61c), to give the titlephenylcarbamate (67 mg). MS found: (M−H)⁻=656.9.

Example 71 Tert-butylN-Methyl-2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl)amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate

(71a) N-Methyl-2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoicacid (106 mg) was incorporated into Example 61, step (61c), to give thetitle phenylcarbamate (50 mg). MS found: (M+Na)⁺=678.2.

Example 72 Ethyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate

(72a) 2-(Ethyloxycarbonyl)amino-5-trifluoromethyl benzoic acid (61 mg)was incorporated into Example 61, step (61c), to give the titlephenylcarbamate (12 mg). MS found: (M+Na)⁺=636.1.

Example 732-(Benzylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(73a) 2-(Benzylamino)-5-trifluoromethyl benzoic acid (65 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(45 mg). MS found: (M+Na)⁺=654.2.

Example 742-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(74a) 2-(Ethylamino)-5-trifluoromethyl benzoic acid (51 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(45 mg). MS found: (M+Na)⁺=592.1.

Example 752-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(75a) 2-(Methylamino)-5-trifluoromethyl benzoic acid (25 mg) wasincorporated into Example 61, step (61c), to give the title benzamide (8mg). MS found: (M+Na)⁺=578.2.

Example 762-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-bromobenzamide (76a) 2-Amino-5-bromo benzoic acid (79 mg) was incorporatedinto Example 61, step (61c), to give the title benzamide (69 mg). MSfound: (M+H)⁺=554.1. Example 77 Tert-butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino)cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethoxy)phenylcarbamate

(77a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethoxybenzoic acid (42mg) was incorporated into Example 61, step (61c), to give the titlephenylcarbamate (45 mg). MS found: (M+Na)⁺=680.2.

Example 782-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethoxybenzamide

(78a) The material from above, (77a), (25 mg) was dissolved in CH₂Cl₂ (3mL) prior to the addition of TFA (1.5 mL). After 1 h, the solution wasconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide (20 mg). MS found: (M+Na)⁺=580.1.

Example 792-(Allylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(79a) 2-(allylamino)-5-trifluoromethyl benzoic acid (50 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(62 mg). MS found: (M+Na)⁺=604.1.

Example 802-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(80a) 2-((2-methyl-2-propenyl)amino)-5-trifluoromethyl benzoic acid (52mg) was incorporated into Example 61, step (61c), to give the titlebenzamide (40 mg). MS found: (M+Na)⁺=618.1.

Example 812-(cyclopropylmethylene)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(81a) 2-(cyclopropylmethylene)amino-5-trifluoromethyl benzoic acid (52mg) was incorporated into Example 61, step (61c), to give the titlebenzamide (20 mg). MS found: (M+Na)⁺=618.2.

Example 822-(butyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(82a) 2-(butyl)amino-5-trifluoromethyl benzoic acid (53 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(20 mg). MS found: (M+Na)⁺=620.1.

Example 832-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(83a) 2-(propyl)amino-5-trifluoromethyl benzoic acid (50 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(59 mg). MS found: (M+Na)⁺=606.2.

Example 842-((2-methyl-2-propyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(84a) 2-((2-methyl-2-propyl)amino)-5-trifluoromethyl benzoic acid (50mg) was incorporated into Example 61, step (61c), to give the titlebenzamide (50 mg). MS found: (M+Na)⁺=620.2.

Example 852-((aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(85a) 2-(aminocarbonyl)amino-5-trifluoromethyl benzoic acid (60 mg) wasincorporated into Example 61, step (61c), to give the title benzamide (7mg). MS found: (M+Na)⁺=665.1.

Example 862-(acetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(86a) 2-acetylamino-5-trifluoromethyl benzoic acid (77 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(35 mg). MS found: (M+H)⁺=642.1.

Example 872-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide

(87a) 2-Methylamino-5-iodo benzoic acid (127 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (20 mg). MS found:(M+H)⁺=614.1.

Example 882-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide

(88a) 2-Ethylamino-5-iodo benzoic acid (100 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (25 mg). MS found:(M+H)⁺=628.1.

Example 892-(Trifluoroacetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethylbenzamide

(89a) 2-Trifluoroacetylamino-5-iodo benzoic acid (77 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(44 mg). MS found: (M+H)⁺=696.1.

Example 902-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-nitrobenzamide

(90a) 2-amino-5-nitro benzoic acid (28 mg) was incorporated into Example61, step (61c), to give the title benzamide (15 mg). MS found:(M+H)⁺=519.1.

Example 91 Iso-propyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate

(91a) 2-(Iso-propoxycarbonyl)amino-5-iodobenzoic acid (73 mg) wasincorporated into Example 61, step (61c), to give the title benzamide(10 mg). MS found: (M+Na)⁺=686.2.

Example 92 Tert butyl2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl)amino)carbonyl]-4-(iodo)phenylcarbamate

(92a) 2-(Tert-butoxycarbonyl)amino-5-iodobenzoic acid (76 mg) wasincorporated into Example 61, step (61c), to give the title benzamide (9mg). MS found: (M+Na)⁺=722.1.

Example 932-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3,5-dinitrobenzamide

(93a) 2-amino-3,5-dinitro benzoic acid (45.4 mg) was incorporated intoExample 61, step (61c), to give the title benzamide (20 mg). MS found:(M+H)⁺=632.0.

Example 942-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(94a) The material from above, (66a), (20 mg) was dissolved in DMF (5mL) prior to the addition of N-methylmorpholine (6 mg) and isopropylisocyanate (4 mg). After 5 h, the solution was loaded onto an HPLC.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (5 mg). MS found:(M+Na)⁺=649.2.

Example 952-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(95a) The material from above, (66a), (20 mg) was dissolved in THF (2mL) prior to the addition of 2M K₂CO₃ (0.1 mL) and cyclohexane carbonylchloride(0.1 mL). After 15 h, 1 N HCl was added and this was extractedwith ethyl acetate. The ethyl acetate was dried and concentrated.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (15 mg). MS found:(M+H)⁺=652.2.

Example 962-((Cyclopentylmethylenecarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(96a) Cyclopentylacetyl chloride (0.1 mL) was incorporated into Example95, step (95a), to give the title benzamide (10 mg). MS found:(M+H)⁺=652.2.

Example 972-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(97a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (preparedin an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (8 g) was dissolved in THF (125mL) and water (18 mL). After cooling to 0° C., triethyl amine (6.2 mL)was added followed by Cbz₂O (12.8 g). This was warmed to rt and wasstirred for 18 h. Some of the THF was removed before ethyl acetate wasadded. This solution was washed with brine and then 1 N HCl solution(aq). The EtOAc was dried (MgSO₄), filtered, and concentrated. Theresulting residue was dissloved in CH₂Cl₂ (15 mL). After cooling to 0°C., TFA (15 mL) was added dropwise. After 1 h, the reaction wasconcentrated and 1 N HCl was added. This acidic solution was extractedwith Et₂O. The aqueous solution was taken to pH=13 via addition of solidNa₂CO₃. This solution was extracted with EtOAc. The EtOAc was dried(MgSO₄), filtered, and concentrated to give1-(N-benzyloxycarbonyl)-cis-cyclohexane-1,2-diamine (7.9 g). MS found:(M+H)⁺=249.1.

(97b) The material from above1-(N-benzyloxycarbonyl)-cis-cyclohexane-1,2-diamine (5 g) was dissolvedin DMF (100 mL). After cooling to 0° C., 4-methylmorpholine (11 mL) andN-Boc-Gly-OH (4.2 g) were added. BOP Reagent (11.6 g) was added, and themixture was stirred at rt for 18 h. The DMF was removed. EtOAc was addedalong with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl,NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated to givecis-[2[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]amino]cyclohexyl]-carbamicacid benzyl ester (9.6 g). MS found: (M+H)⁺=406.3.

(97c) The material from above (9.6 g) was dissloved in CH₂Cl₂ (20 mL).After cooling to 0° C., TFA (10 mL) was added dropwise. After 1 h, thereaction was concentrated. A portion of this residue (5.5 g) wasdissolved in DMF (65 mL). After cooling to 0° C., 4-methylmorpholine(7.2 mL) and 2-(tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid(4.0 g) were added. BOP Reagent (8.7 g) was added, and the mixture wasstirred at rt for 18 h. The DMF was removed. EtOAc was added along with1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gave[(cis)-2-[[[[(2-(tert-butyloxycarbonylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid benzyl ester (5.9 g). MS found: (M+H)⁺=593.3.

(97d) The material (97c) from above (2 g) was dissloved in CH₂Cl₂ (5mL). After cooling to 0° C., TFA (2.5 mL) was added dropwise. After 1 h,the reaction was concentrated. A portion of the resulting residue (500mg) was dissolved in THF (3 mL) prior to the addition of4-methylmorpholine (0.56 mL). After 5 min, cyclohexanecarbonyl chloride(0.4 mL) was added dropwise. After 30 min, EtOAc and 1 N HCl (aq) wereadded. The EtOAc was dried (MgSO₄), filtered, and concentrated. Thismaterial was dissolved in MeOH (5 mL) prior to the addition of 10% Pd/C(200 mg). A hydrogen balloon was added and the reaction continued tostir. After 1.5 h, the solution was filtered and concentrated to giveN-[2-[[(cis)-2-aminocyclohexyl]amino]-2-oxoethyl]-3-(2-cyclohexylcarbonylamino-5-trifluoromethyl)benzamide(202 mg). MS found: (M+H)⁺=469.4.

(97e) The material (97d) from above (50 mg) was dissolved in DMF (2 mL).After cooling to 0° C., 4-methylmorpholine (55.5 mg) andp-(methylsulfonyl)benzoic acid (26 mg) were added. After 5 min, BOPReagent (73 mg) was added and the mixture was stirred at rt for 18 h.The DMF was removed. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) provided thetitle benzamide (15 mg). MS found: (M+H)⁺=651.2.

Example 982-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(98a) 4-(Methylthio)benzoic (28 mg) was incorporated into Example 97,step (97e), to give the title benzamide (20 mg). MS found: (M+H)⁺=619.3.

Example 992-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(99a) Isopropyl isocyanate (0.3 mL) was incorporated into Example 97,step (97d), and reacted for 18 h before being taken forward.Subsequently, 4-(methylthio)benzoic (22 mg) was incorporated intoExample 97, step (97e), to give the title benzamide (20 mg). MS found:(M+H)⁺=594.3.

Example 1002-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(100a) Isopropyl isocyanate (0.3 mL) was incorporated into Example 97,step (97d), and reacted for 18 h before being taken forward.Subsequently, 4-(methylsulfonyl)benzoic (26 mg) was incorporated intoExample 97, step (97e), to give the title benzamide (9 mg). MS found:(M+H)⁺=541.2.

Example 1012-((Methylsulfonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(101a) Methanesulfonyl chloride (0.3 mL) and pyridine (35 mg) wereincorporated into Example 97, step (97d), and reacted for 18 h beforebeing taken forward. Subsequently, p-sulfamylbenzoic (43 mg) wasincorporated into Example 97, step (97e), to give the title benzamide(30 mg). MS found: (M+H)⁺=620.1.

Example 1022-((Aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(102a) Sodium cyanate (0.3 mL) in acetic acid and water wereincorporated into Example 97, step (97d), and reacted for 1 h before theprecipitated solid was taken forward. Subsequently, p-sulfamylbenzoic(24 mg) was incorporated into Example 97, step (97e), to give the titlebenzamide (20 mg). MS found: (M+H)⁺=585.2.

Example 103 2-Allylamino-5-trifluoromethylbenzoic acid

(103a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid (3.0g) was dissolved in DMF prior to the addition of K₂CO₃ (2.4 g) andiodomethane (0.8 mL). After 1.5 h, the solution was diluted with EtOAcand was washed with brine solution followed by 1N HCl solution. Theorganic layer was then washed with Na₂CO₃ solution, water, and brine.The organic layer was dried (MgSO₄), filtered, and concentrated to givethe ester as a off-white solid (3.03 g). A portion of this solid wasdissolved in TFA (3.3 mL) and cooled to 0° C. prior to the addition ofTFAA (0.97 mL). After 10 min, crushed ice was added. After an additional30 min, the solid was collected and washed with water. The solid wasdried to give the TFA amide (970 mg). A portion of this solid (385 mg)was dissolved in DMF (2 mL) and K₂CO₃ (338 mg) was added followed byallyl bromide (1.21 mL). The reaction was stirred 18 h before it wasdiluted with EtOAc and washed with 1N HCl and brine. The EtOAc wasdried, filtered, and concentrated. The resulting residue was dissolve inTHF (10 mL) prior to addition of 1N LiOH (10 mL) and 20 drops of MeOH.After 18 h, the THF was removed and the solution was made acidic (pH=5)with 1N HCl. This solution was extracted with EtOAc. The organic layerwas washed with brine, dried, filtered, and concentrated to give2-allylamino-5-trifluoromethylbenzoic acid (265 mg). MS found:(M+H)⁺=246.2.

Example 1042-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(104a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (preparedin an analogous fashion toN-tert-butyloxycarbonyl-cyclohexane-(S,S)-1,2-diamine, see: C. Wu etal., Bioorg. Med. Chem. 1997, 5, 1925) (6 g) was dissolved in DMF (80mL). After cooling to 0° C., 4-methylmorpholine (15.4 mL) andN-Cbz-Gly-OH (7.03 g) were added. BOP Reagent (18.6 g) was added, andthe mixture was stirred at rt for 18 h. EtOAc was added along with 1 NHCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution,and brine. The EtOAc was dried (MgSO₄), filtered, and concentrated.Flash chromatography of the resulting residue gavecis-[2[[[[(benzyloxy)carbonyl]amino]acetyl]amino]cyclohexyl]-carbamicacid tert-butyl ester (6.2 g). MS found: (M+H)⁺406.3.

(104b) The material from above (9.6 g) was dissloved in MeOH (60 mL)prior to the addition of 10% Pd/C (1.5 g). A hydrogen balloon was addedand the solution was stirred for 18 h. The palladium was filtered offand the filtrate was concentrated. A portion (301 mg) of the resultingresidue was dissolved in DMF (5 mL). After cooling to 0° C.,4-methylmorpholine (0.5 mL) and 2-allylamino-5-trifluoromethylbenzoicacid (Example 103) (226 mg) were added. BOP Reagent (613 mg) was added,and the mixture was stirred at rt for 18 h. EtOAc was added along with 1N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting gave[(cis)-2-[[[[(2-(allylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid tert-butyl ester (364 mg). MS found: (M+Na)⁺521.2.

(104c) The material (104b) from above (360 mg) was dissloved in 4MHCl/dioxane(10 mL). After stirring for 2 h, the solution wasconcentrated. A portion (50 mg) of the resulting residue was dissolvedin DMF (2.5 mL). After cooling to 0° C., 4-methylmorpholine (58 mg) and4-methylsulfonylbenzoic acid (28 mg) was added. BOP Reagent (76 mg) wasadded, and the mixture was stirred at rt for 18 h. EtOAc was added alongwith 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (15 mg). MS found:(M+H)⁺=581.3.

Example 1052-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(105a) 4-(Methylthio)benzoic (168 mg) was incorporated into Example 104,step (104c), to give the title benzamide (20 mg). MS found:(M+H)⁺=549.3.

Example 1062-((2-Methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(106a) 3-Bromo-2-methylpropene was substituted for allyl bromide inExample 103 to give2-(2-methyl-2-propenyl)amino-5-trifluoromethylbenzoic acid, which wasincorporated into Example 104, step (104b), to give the title benzamide(20 mg). MS found: (M+H)⁺=595.2

Example 1072-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(107a) 3-Bromo-2-methylpropene was substituted for allyl bromide inExample 103 to give2-(2-methyl-2-propenyl)amino-5-trifluoromethylbenzoic acid, which wasincorporated into Example 104, step (104b). Subsequently,4-(methylthio)benzoic (168 mg) was incorporated into Example 104, step(104c), to give the title benzamide (20 mg). MS found: (M+H)⁺=563.3.

Example 1082-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(108a) For this preparation, Example 104, step 104c, was altered asfollows.[(Cis)-2-[[[[(2-(allylamino)-5-trifluoromethyl)-benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid tert-butyl ester from 104(b) (360 mg) was dissloved in 4MHCl/dioxane(10 mL). After stirring for 2 h, the solution wasconcentrated. A portion (300 mg) of the resulting residue was dissolvedin MeOH (5 mL) and 10% Pd/C was added. A hydrogen balloon was added andthe solution was stirred for 2 h. The palladium was filtered and thesolution was concentrated. A portion (50 mg) of the resulting residuewas dissolved in DMF (2.5 mL). After cooling to 0° C.,4-methylmorpholine (63 mg) and 4-methylsulfonylbenzoic acid (30 mg) wereadded. BOP Reagent (83 mg) was added, and the mixture was stirred at rtfor 18 h. EtOAc was added along with 1 N HCl solution. The EtOAc layerwas washed with 1 N HCl, NaHCO₃ solution, and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) provided the title benzamide(15 mg). MS found: (M+H)⁺=583.3.

Example 1092-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(109a) 4-(Methylthio)benzoic (25 mg) was incorporated into Example 108to give the title benzamide (10 mg). MS found: (M+H)⁺=551.3.

Example 1102-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(110a)[(Cis)-2-[[[[(2-((2-methyl-2-propenyl)amino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid tert-butyl ester was incorporated into Example 108 to give thetitle benzamide (15 mg). MS found: (M+H)⁺=597.3.

Example 1112-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(111a) 4-(Methylthio)benzoic (25 mg) was incorporated into Example 110to give the title benzamide (10 mg). MS found: (M+H)⁺=565.3.

Example 1122-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(112a) 2-Butylamino-5-trifluoromethylbenzoic acid (prepared analogouslyto Example 103 with butyl iodide) was incorporated into Example 104,step (104b), to give the title benzamide (25 mg). MS found:(M+H)⁺=597.2.

Example 1132-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(113a) 4-(Methylthio)benzoic (22 mg) was incorporated into Example 112to give the title benzamide (25 mg). MS found: (M+H)⁺=565.3.

Example 1142-((Ethylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(114a)[(Cis)-2-[[[[(2-(tert-butyloxycarbonylamino)-5-trifluoromethyl)benzoyl]amino]acetyl]amino]cyclohexyl]carbamicacid benzyl ester (Example 97c) (1.4 g) was dissolved in 4M HCl/dioxane.After stirring at rt for 3h, the reaction was concentrated. A portion ofthis residue (500 mg) was dissolved in MeOH (5 mL) prior to the additionof 10% Pd/C. A hydrogen balloon was added and the solution was stirredfor 3 h. The palladium was filtered and the solution was concentrated.The resulting residue was cooled to 0° C. prior to the addition of4-methylmorpholine (0.55 mL) and 4-(methylthio)benzoic acid (168 mg).BOP Reagent (531 mg) was added, and the mixture was stirred at rt for 18h. The DMF was removed. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave2-(amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide (360 mg). MS found: (M+H)⁺=509.2.

(114b)2-(amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide (Example 114a) (50 mg) was dissolved in THF (2.5 mL) prior tothe addition of triethylamine (30 mg) and ethyl isocyanate (21 mg).After stirring for 72 h, EtOAc was added along with 1 N HCl solution.The EtOAc layer was washed with 1 N HCl and brine. The EtOAc was dried(MgSO₄), filtered, and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) provided the title benzamide(10 mg). MS found: (M+Na)⁺=602.4.

Example 1152-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(115a) Allyl isocyanate (25 mg) was incorporated into Example 114, step(114b), to give the title benzamide (10 mg). MS found: (M+H)⁺=592.3.

Example 1162-((2-methylpropyl)aminocarbonyl)amino-5-trifluoromethylbenzoic acid

(116a) 2-Amino-5-trifluoromethylbenzoic acid (3.75 g) was dissolved inDMF (20 mL) prior to the addition of K₂CO₃ (3.78 g) and allyl bromide(2.4 mL). After 3 h, the solution was diluted with EtOAc and was washedwith brine solution and water. The organic layer was dried (MgSO₄),filtered, and concentrated. Flash chromatography of the resultingresidue gave the allyl ester as a yellow oil (2.6 g). This ester wasdissolved in THF (6 mL) and added dropwise to a THF (3.5 mL) solution oftrichloromethyl chloroformate (1.1 mL). After stirring for 18 h, thesolution was concentrated. A portion (1.4 g) of the resulting residuewas dissolved in THF (2.2 mL) prior to the addition of iso-butylamine(0.95 mL) in THF (3 mL). After 4 h, the solution was diluted with EtOAcand was washed with brine solution and 1N HCl. The organic layer wasdried (MgSO₄), filtered, and concentrated to a white solid. This solidwas dissolved in CH₃CN (30 mL) prior to the addition of pyrrolidine(0.23 mL) and Pd(PPh)₄ (64 mg). After 3 h, the solution was diluted withEtOAc and was washed 1N HCl. The organic layer was dried (MgSO₄),filtered, and concentrated to2-((2-methylpropyl)aminocarbonyl)amino-5-trifluoromethylbenzoic acid(386 mg) as a white solid. MS found: (2M−H)⁻=607.3.

Example 1172-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(117a) 1-(N-tert-Butyloxycarbonyl)-cis-cyclohexane-1,2-diamine (6 g) wasdissolved in DMF (100 mL). After cooling to 0° C, 4-methylmorpholine(15.4 mL) and p-(methylthio)benzoic acid (5.2 g) were added. BOP Reagent(15.0 g) was added, and the mixture was stirred at rt for 18 h. The DMFwas removed. EtOAc was added along with 1 N HCl solution. The EtOAclayer was washed with 1 N HCl, NaHCO₃ solution, and brine. The EtOAc wasdried (MgSO₄), filtered, and concentrated. Flash chromatography of theresulting residue gave tert-butyl(cis)-2-{[4-(methylthio)benzoyl]amino}cyclohexylcarbamate (8.4 g). MSfound: (2M+Na)⁺=751.3.

(117b) The material, 117a, from above (8.4 g) was dissloved in 4MHCl/dioxane. After 3 h, the solution was concentrated. The resultingresidue was dissolved in DMF (50 mL). After cooling to 0° C.,4-methylmorpholine (12.6 mL) and N-Boc-glycine (4.8 g) were added. BOPReagent (15.3 g) was added, and the mixture was stirred at rt for 18 h.The DMF was removed. EtOAc was added along with 1 N HCl solution. TheEtOAc layer was washed with 1 N HCl, NaHCO₃ solution, and brine. TheEtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave tert-butyl2-[((cis)-2-{[4-(methylthio)benzoyl]amino}cyclohexyl)amino]-2-oxoethylcarbamate (9.4 g). MS found: (M+Na)⁺=444.4.

(117c) A portion (2.3 g) of the material, (117b), from above wasdissloved in 4M HCl/dioxane. After 3 h, the solution was concentrated. Aportion of the resulting material (100 mg) was dissolved in DMF (5 mL).After cooling to 0° C., 4-methylmorpholine (0.15 mL) was added followedby 2-((2-methylpropyl)aminocarbonyl)amino-5-trifluoromethylbenzoic acid(Example 116) (26 mg). After 5 min, BOP Reagent (161 mg) was added andthe mixture was stirred at rt for 18 h. The DMF was removed. EtOAc wasadded along with 1 N HCl solution. The EtOAc layer was washed with 1 NHCl, NaHCO₃ solution, and brine. The EtOAc was dried (MgSO₄), filtered,and concentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (50 mg). MS found:(M+H)⁺=608.3.

Example 1182-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(118a) 2-(cyclopentylaminocarbonyl)amino-5-trifluoromethylbenzoic acid(made analogously to Example 116 with cyclopentylamine in place ofiso-butylamine) (88.6 mg) was incorporated into Example 117, step(117c), to give the title benzamide (50 mg). MS found: (M+H)⁺=620.3.

Example 1192-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(119a) 2-(Tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic acid(Takagishi et al., Synlett 1992, 360) (88.6 mg) was incorporated intoExample 117, step (117c), to give the title benzamide (25 mg). MS found:(M+H)⁺=609.3.

Example 1202-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(120a) 2-(Iso-propoxycarbonyl)amino-5-trifluoromethylbenzoic acid (98mg) was incorporated into Example 117, step (117c), to give the titlebenzamide (20 mg). MS found: (M+H)⁺=595.3.

Example 1212-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide (121a) 2-(Ethoxycarbonyl)amino-5-trifluoromethylbenzoic acid(96 mg) was incorporated into Example 117, step (117c), to give thetitle benzamide (30 mg). MS found: (M+H)⁺=581.3. Example 122N-[2-[(1-Pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine

(122a) 2-(Pyrrolidinylcarbonyl)amino-5-trifluoromethylbenzoic acid (madeanalogously to Example 116 with pyrrolidine in place of iso-butylamine(2.9 g) was dissolved in DMF (40 mL). After cooling to 0° C.,4-methylmorpholine (3.2 mL) and glycine benzyl ester hydrogen chloride(5.6 g) were added. After 5 min, BOP Reagent (5.6 g) was added and themixture was stirred at rt for 18 h. EtOAc was added along with 1 N HClsolution. The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution, andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated to asolid (2.6 g). This solid was dissolved in MeOH (14 mL) prior to theaddition of 10% Pd/C. A hydrogen balloon was added and the solution wasstirred for 1 h. The palladium was filtered and the solution wasconcentrated to give the title glycine derivative (2.0 g) as a whitesolid. MS found: (M+H)⁺=360.2.

Example 1232-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(123a) Tert-butyl(cis)-2-{[4-(methylthio)benzoyl]amino}cyclohexylcarbamate (117a) wasdissolved in CH₂Cl₂ (5 mL) and cooled to 0° C. TFA (5 mL) was added andthe solution was stirred. After 1 h, the solution was concentrated. Aportion of the resulting residue (80 mg) was dissolved in DMF (2 mL).After cooling to 0° C., 4-methylmorpholine (0.1 mL) andN-[2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(Example 122)(75 mg) were added. After 5 min, BOP Reagent (116 mg) wasadded and the mixture was stirred at rt for 18 h. EtOAc was added alongwith 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (30 mg). MS found:(M+H)⁺=606.5.

Example 1242-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(124a)N-[2-[(l-Morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(made analogously to Example 122 with2-(morpholinylcarbonyl)amino-5-trifluoromethylbenzoic acid, see Example116) (78 mg) was incorporated into Example 123 to give the titlebenzamide (30 mg). MS found: (M+Na)⁺=644.6.

Example 1252-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide

(125a)N-[2-[(1-Azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(made analogously to Example 122 with2-(azetidinylcarbonyl)amino-5-trifluoromethylbenzoic acid, see Example116) (72 mg) was incorporated into Example 123 to give the titlebenzamide (35 mg). MS found: (M+H)⁺=592.5.

Example 126 Tert-butyl(cis)-3-({N-[2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycyl}amino)tetrahydro-2H-pyran-4-ylcarbamate

(126a) 3,4-Epoxytetrahydropyran (Tetrahedron 1974, 4013) (1 g) wasdissolved in MeOH (10 mL) prior to the addition of NaN₃ (3.9 g) andNH₄Cl (3.2 g) in water (1 mL). The mixture was heated at 85° C. for 18h. After cooling, the solution was concentrated prior to the addition ofCH₂Cl₂ (100 mL). The solids were filtered away and the filtrate wasconcentrated. The resulting residue was dissolved in EtOAc (10 mL)followed by the addition of Boc₂O (3 g) and 20% Pd(OH)₂ (500 mg). Ahydrogen balloon was added and the mixture was stirred for 2 h. EtOAcwas added and the solution was filtered before concentration. Flashchromatography of the resulting residue gavetrans-4-(tert-butoxycarbonyl)aminotetrahydro-2H-pyran-3-ol (see also J.Med. Chem. 2001, 725) (900 mg). MS found: (M+H)⁺=218.1.

(126b) The pyran-3-ol (900 mg) from above, Example 126a, was dissolvedin CH₂Cl₂ and prior to the addition of triethylamine (1.73 mL). Aftercooling to 0° C., methanesulfonyl chloride (0.48 mL) was added dropwise.The solution was stirred for 2 h before 1N HCl was added. The organiclayer was washed with 1 N HCl, NaHCO₃ solution, and brine. The organiclayer was dried (MgSO₄), filtered, and concentrated. The resultingresidue was dissolved in DMSO (10 mL) prior to the addition of NaN₃ (1.3g). The solution was heated at 85° C. for 18 h. After cooling, EtOAc andwater were added. The water layer was extracted with EtOAc. The EtOAcwas washed with brine, dried, and concentrated. Flash chromatography ofthe resulting residue gavecis-3-azido-4-(tert-butoxycarbonyl)aminotetrahydro-2H-pyran (430 mg),which was taken forward. This solid was dissolved in MeOH (10 mL) priorto the addition of 10% Pd/C (300 mg). A hydrogen balloon was added andthe solution was stirred for 1 h. The palladium was filtered and thesolution was concentrated. A portion of the resulting residue (50 mg)was dissolved in DMF (2 mL). After cooling to 0° C., 4-methylmorpholine(0.13 mL) andN-[2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(Example 122)(91 mg) were added. After 5 min, BOP Reagent (132 mg) wasadded and the mixture was stirred at rt for 18 h. EtOAc was added alongwith 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO₃solution, and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue gave thetitle compound (140 mg). MS found: (M+Na)⁺=580.5.

Example 1272-{[1-Pyrrolidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(127a) The carbamate (140 mg) from above, Example 126, was dissolved inCH₂Cl₂ (10 mL) and TFA (10 mL). After 0.5 h, the solution wasconcentrated. A portion (50 mg) of this residue was dissolved in THF (2mL) prior to the addition of acetic acid (0.5 mL) and4-(methylthio)benzaldehyde (20 mg). After 30 min, NaHB(OAc)₃ (27 mg) wasadded and the solution was stirred for 2 h. The solution was filteredand reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) provided the title benzamide (7 mg). MS found:(M+H)⁺=594.5.

Example 128 Tert-butyl(cis)-3-({N-[2-[(1-azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycyl}amino)tetrahydro-2H-pyran-4-ylcarbamate

(128a)N-[2-[(l-Azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine(made analogously to Example 122 with2-(azetidinylcarbonyl)amino-5-trifluoromethylbenzoic acid, see Example116) (209.3 mg) was incorporated into Example 126 to give the titlecarbamate (123.7 mg). MS found: (M+Na)⁺=566.4.

Example 1292-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(129a) The carbamate (80 mg), Example 128, from above was incorporatedinto Example 127 to give the title benzamide (11 mg). MS found:(M+H)⁺=580.5.

Example 1302-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(130a) Anisaldehyde (43 mg) was incorporated into Example 129 to givethe title benzamide (36 mg). MS found: (M+H)⁺=564.4.

Example 1311-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane

(131a) (Cis)-N-benzyl-2,2,2-trifluoro-N-(7-oxa-bicyclo[4.1.0]hept-3-yl)acetamide (M. Chini et al., J. Org. Chem. 1990, 55, 4265-4272) (3.7 g)was dissolved in methanol (50 mL) prior to addition of NaN₃ (1.6 g) inH₂O (5 mL). The flask was fitted with a condenser and heated at refluxfor 2 h. The cooled solution was partitioned between EtOAc and water andthe organic layer was washed with NaHCO₃ and brine. The organic layerwas dried, filtered, and concentrated. Flash chromatography of theresulting residue providedN-(3-azido-4-hydroxycyclohexyl)-N-benzyl-2,2,2-trifluoroacetamide (3.1g). MS found: (M+Na)⁺=378.2.

(131b) A portion of the above derivative (131a) (3.1 g) was dissolved inTHF (20 mL) prior to addition of PPh₃ (3.6 g). The solution was stirredat rt for 12 h and water (5 mL) was added. The solution was stirred foran additional 12 h, and partitioned between EtOAc and water. The waterlayer was treated with 2 N NaOH until the pH=9 and was extracted EtOAc(3×). The combined organic extracts were dried, filtered andconcentrated. The residue was partially purified by flash chromatographyand was dissolved in THF (160 mL) and water (40 mL). The solution wastreated with NaHCO₃ (3 g) prior to addition of di-tert-butyl dicarbonate(4.7 g). The solution was stirred for 8 h, partitioned between EtOAc andwater, and the organic layer was washed with NaHCO₃ and brine. Theorganic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided{5-[benzyl-(2,2,2-trifluoroacetyl)amino]-2-hydroxycyclohexyl)carbamicacid tert-butyl ester (3.1 g). MS found: (M+Na)⁺=439.1.

(131c) The above derivative (131b) (3.1 g) was dissolved in methanol(100 mL) prior to addition of KOH (3 g), dissolved in water (50 mL). Theflask was fitted with a condenser and heated at reflux for 2 h. Thecooled solution was partitioned between EtOAc and water. The water layerwas extracted with EtOAc (3×). The combined organic extracts were dried,filtered, and concentrated. The residue was dissolved in methanol (100mL) prior to addition of 5% Pd/C (0.5 g). This reaction was placed on aParr apparatus at 50 psi hydrogen pressure. After shaking for 8 h, thePd/C was filtered off and the solution was concentrated. The residue wasdissolved in THF (80 mL) and water (20 mL). The solution was treatedwith NaHCO₃ (1.7 g) prior to addition of benzyl chloroformate (1.3 mL).The solution was stirred for 8 h, and partitioned between EtOAc andwater. The organic layer was washed with NaHCO₃ and brine. The organiclayer was dried, filtered, and concentrated. Flash chromatography of theresidue provided(3-tert-butoxycarbonylamino-4-hydroxycyclohexyl)carbamic acid benzylester (2.75 g). MS found: (M+Na)⁺=387.2. (131d) A stirred solution ofPPh₃ (2.3 g) was dissolved in THF (20 mL) and cooled to 0° C. prior tothe dropwise addition of DEAD (1.4 mL). The solution was stirred for 0.5h and combined with a solution of the above derivative (131c) (1.6 g) inTHF (10 mL) and 10% HN3 in benzene (10.5 mL). The solution was stirredfor 4 h and partitioned between EtOAc and water. The organic layer waswashed with NaHCO₃ and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the residue provided(2-azido-5-benzyloxycarbonylaminocyclohexyl)carbamic acid tert-butylester (1.6 g). MS found: (M+Na)⁺=412.2.

(131e) The above derivative (131d) (1.5 g) was dissolved in THF (50 mL)prior to addition of PPh₃ (1.5 g). The solution was stirred at rt for 12h and water (5 mL) was added. The solution was stirred for 12 h andpartitioned between EtOAc and water. The water layer was treated with 2N NaOH until the pH=9 and was extracted with EtOAc (3×). The combinedorganic extracts were dried, filtered, and concentrated. Flashchromatography of the residue provided(2-amino-5-benzyloxycarbonylaminocyclohexyl)carbamic acid tert-butylester (1.1 g). MS found: (M+H)⁺=364.2.

(131f) A portion of the above derivative (131e) (150 mg) was dissolvedin DMF (2 mL) prior to addition of Hunig's base (0.5 mL).4-(thiomethyl)benzoic acid (140 mg) was added followed by HATU (470 mg).The solution was stirred for 8 h then quenched with aqueous NH₄Cl. Themixture was partitioned between EtOAc and water. The organic layer waswashed with NaHCO₃, 5% LiCl (3×), and brine. The organic layer wasdried, filtered, and concentrated. Flash chromatography of the residueprovided[3-tert-butoxycarbonylamino-4-(4-methylthio-benzoylamino)cyclohexyl]carbamicacid benzyl ester (198 mg). MS found: (M+H)⁺=514.2.

(131g) A portion of the above derivative (131f) (198 mg) was dissolvedin CH₂Cl₂ (10 mL) prior to addition of TFA (10 mL). The solution wasstirred for 4 h, and concentrated. The residue was dissolved in DMF (2mL) prior to addition of Hunig's base (0.5 mL).(2-tert-Butoxycarbonylamino-5-trifluoromethylbenzoylamino)acetic acid(181 mg) was added followed by HATU (470 mg). The solution was stirredfor 8 h and quenched with aqueous NH₄Cl. The mixture was partitionedbetween EtOAc and water. The organic layer was washed with NaHCO₃, 5%LiCl (3×), and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the residue provided[2-({[5-benzyloxycarbonylamino-2-(4-methylthio-benzoylamino)cyclohexylcarbamoyl]-methyl}carbamoyl)-4-trifluoromethylphenyl]carbamicacid tert-butyl ester (250 mg). MS found: (M+H)⁺=758.1.

(131h) A portion of the above derivative (131g) (250 mg) was dissolvedin HOAc (3 mL) prior to addition of 38% HBr (3 mL). The solution wasstirred for 12 h and poured into NaHCO₃ (100 mL). The solution wasadjusted to pH=9 with 2 N NaOH and extracted with EtOAc. The organiclayer was dried, filtered, and concentrated. Flash chromatography of theresidue provided the title compound (120 mg). MS found: (M+H)⁺=524.3.

Example 132{4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane

(132a) (3-Trifluoromethylbenzoylamino) acetic acid (77 mg) wasincorporated into Example 131, step (131g). Flash chromatography of theresidue provided{4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester (47 mg). MS found: (M+H)⁺=643.2.

(132b) A portion of the above derivative (132a) (16 mg) was incorporatedinto Example 131, step (131h). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (8 mg). MS found: (M+H)⁺=509.2.

Example 1331-(4-Methanesulfonylbenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl-4-aminocyclohexane

(133a) A portion of the above derivative (132a) (51 mg) was dissolved inCH₂Cl₂ (20 mL) prior to addition of K₂CO₃ (138 mg) and 50% m-CPBA (86mg). The mixture was stirred for 8 h and quenched with aqueous sodiumthiosulfate. The organic layer was washed with NaHCO₃ and brine. Theorganic layer was dried, filtered, and concentrated. The residue wasdissolved in CH₂Cl₂ (10 mL) prior to addition of TFA (10 mL). Thesolution was stirred for 4 h and concentrated. The residue was dissolvedin DMF (2 mL) prior to addition of Hunig's base (0.2 mL).(3-trifluoromethylbenzoylamino)acetic acid (77 mg) was added followed byHATU (150 mg). The solution was stirred for 8 h, and quenched withaqueous NH₄Cl. The mixture was partitioned between EtOAc and water. Theorganic layer was washed with NaHCO₃, 5% LiCl (3×), and brine. Theorganic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided{4-(4-Methanesulfonylbenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid benzyl ester (41 mg). MS found: (M+H)⁺=675.2.

(133b) A portion of the above derivative (133a) (35 mg) was incorporatedinto Example 131, step (131h). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (14 mg). MS found: (M+H)⁺=541.2.

Example 1341-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)cyclohexane

(134a) A portion of the above derivative (131h) (35 mg) was dissolved inmethanol (0.5 mL) prior to addition of HC(OCH₃)₃ (2 mL) and acetone (0.2mL). The solution was stirred for 1 h and NaBH(OAc)₃ (100 mg) was added.The solution was stirred for 12 h and poured into NaHCO₃ (10 mL). Thesolution was adjusted to pH=9 with 2 N NaOH and extracted with EtOAc.The organic layer was dried, filtered, and concentrated. Reverse phaseHPLC purification (gradient elution, water/acetonitrile/TFA) of theresidue provided the title compound (14 mg). MS found: (M+H)⁺=566.1.

Example 1351-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(3-methylureido)cyclohexane

(135a) A portion of the above derivative (131h) (35 mg) was dissolved inCH₂Cl₂ (5 mL) prior to addition of Hunig's base (0.2 mL). Methylisocyanate (40 mg) was added and the solution was stirred for 4 h. Thesolution was poured into NaHCO₃ (10 mL) and EtOAc 20 mL). The organiclayer was dried, filtered and concentrated. Reverse phase HPLCpurification (gradient elution, water/acetonitrile/TFA) of the residueprovided the title compound (10 mg). MS found: (M+H)⁺=581.0.

Example 1361-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-aminocyclohexane

(136a) A portion of the above derivative (131e) (100 mg) was dissolvedin DMF (2 mL) prior to addition of Hunig's base (0.3 mL).(3-trifluoromethyl-benzoylamino)-acetic acid (136 mg) was added followedby HATU (310 mg). The solution was stirred for 8 h and quenched withNH₄Cl. The mixture was partitioned between EtOAc and water. The organiclayer was washed with NaHCO₃, 5% LiCl (3×), and brine. The organic layerwas dried, filtered and concentrated. Flash chromatography of theresidue provided{5-benzyloxycarbonylamino-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamicacid tert-butyl ester (140 mg). MS found: (M+H)⁺=593.3.

(136b) A portion of the above derivative (136a) (136 mg) was dissolvedin CH₂Cl₂ (10 mL) prior to addition of TFA (10 mL). The solution wasstirred for 4 h, and concentrated. The residue was dissolved in DMF (2mL) prior to addition of Hunig's base (0.3 mL). 4-(thiomethyl)benzoicacid (77 mg) was added followed by HATU (262 mg). The solution wasstirred for 8 h and quenched with aqueous NH₄Cl. The mixture waspartitioned between EtOAc and water. The organic layer was washed withNaHCO₃, 5% LiCl (3×), and brine. The organic layer was dried, filtered,and concentrated. Flash chromatography of the residue provided{3-(4-methylthiobenzoylamino)-4-[2-(3-trifluoromethylbenzoylamino)acetylamino]cyclohexyl}carbamicacid benzyl ester (56 mg). MS found: (M+H)⁺=643.3.

(136c) A portion of the above derivative (136b) (31 mg) was incorporatedinto Example 131, step (131h). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (22 mg). MS found: (M+H)⁺=509.2.

Example 1371-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-(2-propylamino)cyclohexane

(137a) A portion of the above derivative (136c) (15 mg) was incorporatedinto Example 134, step (134a). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (13 mg). MS found: (M+H)⁺=551.0.

Example 1381-(4-Methylthio-benzoylamino)-2-[2-(2-Amino-5-trifluoromethyl-benzoylamino)-acetylamino]-4-aminocyclohexane

(138a)(Cis)-N-benzyl-2,2,2-trifluoro-N-(7-oxa-bicyclo[4.1.0]hept-3-yl)acetamide(M. Chini et al., J. Org. Chem. 1990, 55, 4265-4272) (1.2 g) wasincorporated into Example 131, step (131a). The residue was purified byflash chromatography to provideN-(4-azido-3-hydroxycyclohexyl)-N-benzyl-2,2,2-trifluoroacetamide (785mg). MS found: (M+Na)⁺=378.2.

(138b) A portion of the above derivative (138a) (785 mg) wasincorporated into Example 131, step (131b). The residue was purified byflash chromatography to provide{4-[benzyl-(2,2,2-trifluoroacetyl)-amino]-2-hydroxycyclohexyl}carbamicacid tert-butyl ester (765 mg). MS found: (M−H)⁻=415.0.

(138c) A portion of the above derivative (138b) (765 mg) wasincorporated into Example 131, step (131c). The residue was purified byflash chromatography to provide(4-tert-butoxycarbonylamino-3-hydroxycyclohexyl)carbamic acid benzylester (580 mg). MS found: (M+H)⁺=365.2.

(138d) A portion of the above derivative (138c) (530 mg) wasincorporated into Example 131, step (131d). The residue was purified byflash chromatography to provide(2-azido-4-benzyloxycarbonylaminocyclohexyl)carbamic acid tert-butylester (480 mg). MS found: (M+Na)⁺=412.2.

(138e) A portion of the above derivative (138d) (380 mg) wasincorporated into Example 131, step (131e). The residue was purified byflash chromatography to provide(3-amino-4-tert-butoxycarbonylaminocyclohexyl)carbamic acid benzyl ester(320 mg). MS found: (M+H)⁺=364.2.

(138f) The above derivative (138e) (80 mg) was incorporated into Example131, step (131g). Flash chromatography of the residue provided{4-benzyloxycarbonylamino-2-[2-(2-tert-butoxycarbonylamino-5-trifluoromethylbenzoylamino)acetylamino]cyclohexyl)carbamicacid tert-butyl ester (97 mg). MS found: (M−H)⁻=706.4.

(138g) The derivative (138f) (97 mg) was incorporated into Example 136,step (136b). Flash chromatography of the residue provided[3-[2-(2-amino-5-trifluoromethyl-benzoylamino)acetylamino]-4-(4-methylsulfanylbenzoylamino)cyclohexyl]carbamicacid benzyl ester (80 mg). MS found: (M+H)⁺=658.2.

(138h) The derivative (138g) (60 mg) was incorporated into Example 131,step (131h): Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (16mg). MS found: (M+H)⁺=524.3.

Example 1394-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-aminocyclohexane

(139a) A portion of the above derivative (138e) (50 mg) incorporatedinto Example 136, step (136b). The organic layer was dried, filtered,and concentrated. Flash chromatography of the residue provided{4-benzyloxycarbonylamino-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl}carbamicacid tert-butyl ester (74 mg). MS found: (M+H)⁺=593.3.

(139b) A portion of the derivative (139a) (70 mg) was incorporated intoExample 136, step (136b) Reverse phase HPLC purification (gradientelution) of the residue provided{4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl)carbamicacid benzyl ester (20 mg). MS found: (M+H)⁺=643.2.

(139c) A portion of the above derivative (139b) (60 mg) was incorporatedinto Example 131, step (131h). Reverse phase HPLC purification (gradientelution, water/acetonitrile/TFA) of the residue provided the titlecompound (28 mg). MS found: (M+H)⁺=509.3.

Example 1404-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)-cyclohexane

(140a) The derivative (139c) (15 mg) was incorporated into Example 134,step (134a). Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (11mg). MS found: (M+H)⁺=551.2.

Example 1411-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-5-aminocyclohexane

(141a) The derivative (138e) (35 mg) was incorporated into Example 131,step (131f). Flash chromatography of the residue provided[4-benzyloxycarbonylamino-2-(4-methylthiobenzoylamino)cyclohexyl]carbamicacid tert-butyl ester (44 mg). MS found: (M+H)⁺=514.2.

(141b) The above derivative (141a) (40 mg) was incorporated into Example132, step (132a). The residue was triturated with EtOAc and collected ona sintered glass frit to provide the title compound{3-(4-methylthiobenzoylamino)-4-[2-(3-trifluoromethylbenzoylamino)acetylamino]cyclohexyl}carbamicacid benzyl ester (43 mg). MS found: (M+H)⁺=643.3.

(141c) The above derivative (141b) (40 mg) was incorporated into Example131, step (131h). Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (15mg). MS found: (M+H)⁺=509.1.

Example 143 [2-Isopropylamino-5-(trifluoromethyl)]benzoic acid

(143a) Isopropylamine (4.0 mL) was dissolved in THF (20 mL). Thissolution was cooled to 0° C. and n-butyllithium (2.5 M, 20 mL) wasadded. The reaction was stirred for 90 min, then transferred to asolution of [2-fluoro-5-(trifluoromethyl)]benzoic acid (4.2 g) in THF(40 mL) at −78° C. This mixture was stirred for 15 min and the reactionwas quenched with aqueous NH4Cl. The mixture was extracted with EtOAc(3×). The organic layer was dried, filtered, and concentrated. Flashchromatography of the resulting residue provided the title compound (2.4g). MS found: (M+H)⁺=248.2.

Example 1442-Isopropylamino-N-{[(cis)2-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide

(144a) N-tert-Butyloxycarbonylcyclohexane-(cis)-1,2-diamine (518 mg) wasdissolved in CH₂Cl₂ (45 mL) and DMF (15 mL) prior to the addition ofHunig's base (1.7 mL) and([2-(isopropylamino)-5-(trifluoromethyl)benzoylamino]acetic acid(incorporated Example 143 into Example 122) (400 mg) and HATU (1.84 g)at rt. The reaction was stirred for 8h and quenched with water. Theorganic layer was washed with 1 N HCl, aqueous NaHCO₃, 5% aqueous LiCl,and brine. The organic layer was dried, filtered, and concentrated.Flash chromatography of the residue providedcis-{2-[2-(2-isopropylamino-5-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl}carbamicacid tert-butyl ester (534 mg). MS found: (M−Boc+H)⁺=401.1.

(144b) The above derivative (144a) (150 mg) was dissolved in CH₂Cl₂ (12mL) and cooled to 0° C. Trifluoroacetic acid (4 mL) was added and thereaction was warmed to rt, stirred for 1 h and concentrated. The residuewas dissolved in CH₂Cl₂, washed with aqueous NH₄OH, and concentrated.The residue was dissolved in trimethylorthoformate (3 mL) prior to theaddition of 4-methylsulfanylbenzyaldehyde (400 μL). After 6 h, NaBH₄(113 mg) was added. The reaction was stirred for 12 h, quenched withwater and extracted with CH₂Cl₂ (3×). The CH₂Cl₂ layer was washed withaqueous NH₄Cl and brine. The organic layer was dried, filtered, andconcentrated. Flash chromatography of the residue provided2-isopropylamino-N-{[(cis)2-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide(114 mg). MS found: (M+H)⁺=537.2.

Example 1452-(3-Isopropylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide

(145a) [2-(3-Isopropylureido)-5-trifluoromethylbenzoylamino]acetic acidwas incorporated into Example 144, step (144a) to give(2-(cis)-[2-[2-(3-isopropylureido)-5-trifluoromethylbenzoylamino]acetylamino]cyclohexyl)carbamicacid tert-butyl ester (404 mg). MS found: (M−Boc+H)⁺=444.0.

(145b) The above derivative (145a) was incorporated into Example 144,step (144b). Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (75mg). MS found: (M+H)⁺=580.1.

Example 1462-(3-Morpholinylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide

(146a){2-[(Morpholinylcarbonyl)amino]-5-trifluoromethylbenzoylamino}aceticacid was incorporated into Example 144, step (144a) to providecis-[2-(2-{2-[(morpholine-4-carbonyl)-amino]-5-trifluoromethylbenzoylamino}acetylamino)cyclohexyl]carbamicacid tert-butyl ester (606 mg). MS found: (M−Boc+H)⁺=472.0.

(146b) The above derivative (146a) was incorporated into Example 144,step (144b). Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlecompound (58 mg). MS found: (M+H)⁺=608.

Example 1512-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(151a) 1-Tert-butoxycarbonyl-4-azido-3-hydroxy-piperidine (Marquis etal. J. Med. Chem. 2001, 44, 725) (39.6 g) was dissolved in MeOH (500 mL)prior to the addition of 10% Pd/C (10 g) in a Parr bottle. The reactionwas shaken at 50 psi overnight. The reaction was filtered and thevolatiles were removed under reduced pressure. The resulting residue(35.4 g) was dissolved in THF (1000 mL) and water (240 mL) along withEt₃N (68.6 mL) and (Cbz)₂O (52 g). The reaction was stirred at ambienttemperature overnight and the volatiles were removed under reducedpressure. The resulting material was taken into ether and washed with10% aqueous citric acid, water, saturated aqueous sodium bicarbonate,brine, dried over MgSO₄, and the volatiles were removed under reducedpressure. Flash chromatography of the resulting residue gave1-tert-butoxycarbonyl-4-(benzyloxycarbonyl)amino-3-hydroxy-piperidine(37.2 g) as the faster eluting isomer 1e. MS found: (M+Na)⁺=534.5.

(151b) To a stirred, cooled (5° C. water bath) solution of 2.81 grams oftriphenylphosphine in 80 mL of benzene was added 1.82 mL of DEADdropwise over 5 minutes. After stirring 15 minutes at 5° C. a premixedsolution of 3 grams of 151a (from above) in 40 mL THF and 80 mL of ˜2.3molar HN3 in benzene was added over 20 minutes. The reaction was stirredat ambient temperature overnight. Ether was added and the mixture waswashed with saturated aqueous sodium bicarbonate, water, brine and driedover MgSO₄. The volatiles were removed under reduced pressure. Theresulting material (combined from two runs) was dissolved in THF (400mL) and triphenylphosphine (13.5 g) was added along with 4 mL of water.The reaction was stirred at 65° C. for 14 hours and the volatiles wereremoved under reduced pressure. The material was taken into ether andextracted 4 times with 0.1M aqueous HCl. The combined aqueous layerswere washed twice with ether and made basic (pH>9) by the addition ofsodium bicarbonate. The resulting slurry was extracted three times withether, dried over MgSO₄ and the volatiles were removed under reducedpressure affording 3 grams of1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine. MSfound: (M+H)⁺=350.4.

(151c) The above material (151b, 2.0 g) was dissolved in DMF (40 mL)prior to the addition of NMM (1.9 mL),N-[2-[(1-t-butoxycarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine (seeExample 122) (2.3 g), and HATU (2.3 g). After stirring overnight atambient temperature the volatiles were removed under reduced pressureand resulting material was slurried in ether and washed with 10% aqueouscitric acid, water, saturated aqueous sodium bicarbonate, brine, driedover MgSO₄, and the volatiles were removed under reduced pressure. Thisresulted in tert-butyl(cis)-4-{[(benzyloxy)carbonyl]amino}-3-{[1-{[2-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)benzoyl]amino)2-oxoethyl]amino}-1-piperidinecarboxylate(4.05 g). MS found: (M+H)⁺=692.4.

(151d) The above material (151c) (13.4 g) was dissolved in CH₂Cl₂ (50mL) and TFA (50 mL). After stirring for 30 minutes, the volatiles wereremoved under reduced pressure. The resulting residue was dissolved inCH₃CN (200 mL) prior to the addition of potassium carbonate (10.7 g) andallylbromide (1.83 mL). The reaction was stirred at ambient temperatureovernight, the mixture was filtered and the volatiles were removed underreduced pressure. The material was dissolved in ether and washed withwater, saturated aqueous brine, dried over MgSO₄. The volatiles wereremoved under reduced pressure affording benzyl(cis)-1-allyl-3-{[1-{[2-amino-5-(trifluoromethyl)benzoyl]amino)2-oxoethyl]amino}-4-piperidinylcarbamate(8 g). MS found: (M+H)⁺=534.5.

(151e) The above material (151d) (8.0 g) was dissolved in MeOH (100 mL)prior to the addition of 10% Pd/C (8 g). This was stirred under hydrogen(balloon) for 6 hours. The mixture was filtered and the volatilesremoved under reduced pressure. The resulting residue was dissolved inMeOH (250 mL) prior to the addition of 4-methylthiobenzaldehyde (1.78mL), sodium cyanoborohydride (2.0 g), and zinc chloride (4.4 g). Thereaction was stirred at ambient temperature overnight. The volatileswere removed under reduced pressure and resulting material waspartitioned in ether and water. The ether phase was washed with water,then extracted 4× with 0.1N HCl. All the acidic extracts were combinedand washed twice with ether, rendered basic (pH>8.5) by the addition ofsodium bicarbonate, extracted three times with dichloromethane, driedover MgSO₄, and the volatiles were removed under reduced pressure. Theresulting material was chromatographed on silica gel eluting with agradient of 2-5% methanol/chloroform affording 1.8 grams as the mixtureof enantiomers. The mixture was chromatographed on a chiracel OD columneluting with 15% ethanol/hexane. The faster enantiomer was collected,the volatiles were removed under reduced pressure and the resultingmaterial was lypholized from a mixture of water/TFA affording the titlebenzamide (0.98 g). MS found: (M+H)⁺=538.5.

Example 1522-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(152a) The final chiracel OD column from above also gave this enantiomer(second) as the title compound. MS found: (M+H)⁺=538.5.

Example 1532-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(153a) MeI (0.58 mL of 0.10 g/mL solution in CH₃CN) was incorporatedinto Example 151d to give benzyl(cis)-1-methyl-3-{[1-{[2-amino-5-(trifluoromethyl)benzoyl]amino}2-oxoethyl]amino}-4-piperidinylcarbamate(107 mg). LRMS found (M+H)⁺=508.3.

(153b) The above material (153a) (100 mg) was dissolved in MeOH (5 mL)prior to the addition of 10% Pd/C (100 mg). This was stirred underhydrogen (balloon) for 2 hours. The mixture was filtered and thevolatiles removed under reduced pressure. The resulting residue wasdissolved in DMF (1.5 mL) prior to the addition of NMM (0.032 mL),4-methylthiobenzoic acid (0.018 g), and HATU (0.038 g). After stirringovernight at ambient temperature the volatiles were removed underreduced pressure. Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the residue provided the title compound (29mg). MS found: (M+H)⁺=524.4.

Example 154N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(154a) (3-Trifluoromethylbenzoylamino) acetic acid and4-chlorobenzaldehyde were incorporated into Example 151 (without theallyl bromide alkylation of step 151d) to give the title benzamide. MSfound: (M+H)⁺=469.3.

Example 155N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(155a) (3-Trifluoromethylbenzoylamino) acetic acid and4-methylthiobenzaldehyde were incorporated into Example 151 (without theallyl bromide alkylation of step 151d) to give the title benzamide. MSfound: (M+H)⁺=481.2.

Example 1562-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide

(156a) 4-Chlorobenzaldehyde was incorporated into Example 151 (withoutthe allyl bromide alkylation of step 151d) to give the title benzamide.MS found: (M+H)⁺=484.4.

Example 1572-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(157a) 4-Methylthiobenzaldehyde was incorporated into Example 151(without the allyl bromide alkylation of step 151d) to give the titlebenzamide. MS found: (M+H)⁺=496.5.

Example 1582-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide

(158a) 4-Ethylthiobenzaldehyde was incorporated into Example 151(without the allyl bromide alkylation of step 151d) to give the titlebenzamide. MS found: (M+H)⁺=510.5.

Example 159N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(159a) MeI and (3-Trifluoromethylbenzoylamino) acetic acid wereincorporated into Example 151 to give the title benzamide. MS found:(M+H)⁺=493.3.

Example 160N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(160a) The final reverse phase HPLC purification from the procedureabove (159a) also gave the title benzamide. MS found: (M+H)⁺=631.3.

Example 1612-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide

(161a) MeI and was incorporated into Example 151 to give the titlebenzamide. MS found: (M+H)⁺=510.3.

Example 162N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(162a) (3-Trifluoromethylbenzoylamino) acetic acid (substituted in step151c) and acetyl chloride/Et₃N (substituted for allyl bromide/K₂CO₃,step 151d) were incorporated into Example 151 to give the titlebenzamide. MS found: (M+H)⁺=551.4.

Example 1632-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(163a) Crotyl bromide and was incorporated into Example 151 to give thetitle benzamide. MS found: (M+H)⁺=552.5.

Example 1642-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(164a) N-[2-[cyclohexylamino]-5-(trifluoromethyl)benzoyl]glycine (seeExample 143 with cyclohexyl amine and Example 122) was incorporated intoExample 151 to give the title benzamide. MS found: (M+H)⁺=620.6.

Example 1652-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(165a) N-[2-[Iso-propylamino]-5-(trifluoromethyl)benzoyl]glycine (seeExample 143 and Example 122) was incorporated into Example 151 to givethe title benzamide. MS found: (M+H)⁺=580.5.

Example 1662-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(166a) 2-(Pyrrolidinylcarbonyl)amino-5-trifluoromethylbenzoic acid (seeExample 122) was incorporated into Example 151 to give the titlebenzamide. MS found: (M+H)⁺=635.6.

Example 1672-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(167a) 2-(Methylcarbonyl)amino-5-trifluoromethylbenzoic acid (seeExample 122) was incorporated into Example 151 to give the titlebenzamide. MS found: (M+H)⁺=595.6.

Example 1683-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(168a) 3-Amino-5-trifluoromethylbenzoic acid (see Example 122) wasincorporated into Example 151 to give the title benzamide. MS found:(M+H)⁺=538.5.

Example 169N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(169a) 4-Aminosulfonylbenzoic acid (into step 153b) and(3-trifluoromethylbenzoylamino) acetic acid (into step 151c) wereincorporated into Example 151 without step 151d (skip this step) to givethe title benzamide. MS found: (M+H)⁺=528.3.

Example 170N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(170a) 4-Methylsulfonylbenzoic acid was incorporated into Example 169 togive the title benzamide. MS found: (M+H)⁺=527.0.

Example 1712-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(171a)N-[2-[(l-t-butoxycarbonyl)amino]-5-(trifluoromethyl)benzoyl]glycine wasincorporated into Example 153 and step 151d was skipped to give thetitle benzamide. MS found: (M+H)⁺=510.3.

Example 172N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(172a) (3-Trifluoromethylbenzoylamino) acetic acid was incorporated intoExample 153 (by way of 151c) to give the title benzamide. MS found:(M+H)⁺=509.3.

Example 173N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl)-3-(trifluoromethyl)benzamide

(173a) Acetyl chloride/Et₃N was incorporated into Example 172 (via step153a) to give the title benzamide. MS found: (M+H)⁺=559.3.

Example 1742-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide

(174a) Crotyl bromide was incorporated into Example 153 (via step 153a)to give the title benzamide. MS found: (M+H)⁺=566.5.

Example 1752-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(175a) N-[2-[cyclohexylamino]-5-(trifluoromethyl)benzoyl]glycine (seeExample 143 with cyclohexyl amine and Example 122) and allyl bromidewere incorporated into Example 153 to give the title benzamide. MSfound: (M+H)⁺=634.6.

Example 1762-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(176a) N-[2-[iso-propylamino]-5-(trifluoromethyl)benzoyl]glycine (seeExample 143 with i-propylamine and Example 122) and allyl bromide wereincorporated into Example 153 to give the title benzamide. MS found:(M+H)⁺=594.4.

Example 1773-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino)-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide

(177a) N-[3-(amino)-5-(trifluoromethyl)benzoyl]glycine (see Example 122)and allyl bromide were incorporated into Example 153 to give the titlebenzamide. MS found: (M+H)⁺=552.4.

Example 178N-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl)-3-(trifluoromethyl)benzamide

(178a)1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine(151b) (300 mg) was dissolved in DMF (5 mL) prior to addition of Hunig'sbase (0.45 mL). 4-(aminosulfonyl)benzoic acid (210 mg) was addedfollowed by BOP (420 mg). The solution was stirred for 8 h then quenchedwith aqueous NH₄Cl. The mixture was partitioned between EtOAc and water.The organic layer was washed with NaHCO₃, 5% LiCl (3×), and brine. Theorganic layer was dried, filtered, and concentrated. Flashchromatography of the residue provided tert-butyl(cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-{[(benzyloxy)carbonyl]amino}-1-piperidinecarboxylate(210 mg). MS found: (M−H)⁻=531.3.

(178b) The material from above (178a) (200 mg) was dissolved in CH₂Cl₂(2 mL) prior to the addition of Pd(OAc)₂ (28 mg), Et₃SiH (0.29 mL), andEt₃N (0.02 mL). The solution was stirred overnight. This was quench withsaturated NaHCO₃ and extracted with CH₂Cl₂. The organic layer was dried,filtered, and concentrated. The resulting residue was dissolved in DMF(1 mL) prior to addition of NMM (0.032 mL),(3-Trifluoromethylbenzoylamino)acetic acid (see Example 122) (29 mg),and HATU (42 mg). After stirring overnight at ambient temperature thevolatiles were removed under reduced pressure and EtOAc was added. Thiswas washed with 10% aqueous citric acid, water, saturated aqueous sodiumbicarbonate, brine, dried over MgSO₄, and the volatiles were removedunder reduced. This material was dissolved in CH₂Cl₂ (1 mL) prior to theaddition of TFA (1 mL). After 1 h, the solution was concentrated.Reverse phase HPLC purification (gradient elution,water/acetonitrile/TFA) of the resulting residue provided the titlebenzamide. MS found: (M+H)⁺=528.1.

Example 179N-{[4-Dimethylamino-2-(4-methylsulfanyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

(179a) Cis-4-(benzyloxy)-1,2-epoxycyclohexane (6 g) (Chini et al. J.Org. Chem. 1990, 55, 4265) was dissolved in MeOH (160 mL) prior to theaddition of NaN₃ (9.5 g) and NH₄Cl (3.4 g) in water (20 mL). The mixturewas heated at 85° C. for 18 h. After cooling, the solution wasconcentrated prior to the addition of CH₂Cl₂. The solids were filteredaway and the filtrate was concentrated. A portion (500 mg) of theresulting residue was dissolved in EtOAc (10 mL) followed by theaddition of Boc₂O (485 mg) and 20% Pd(OH)₂ (200 mg). A hydrogen balloonwas added and the mixture was stirred for 2 h. EtOAc was added and thesolution was filtered before concentration. This material was dissolvedin CH₂Cl₂ (5 mL) and cooled to 0° C. prior to the addition of Et₃N (0.26mL) and methanesulfonyl chloride (0.3 mL). After 2 h, the CH₂Cl₂ wasremoved and EtOAc was added. This was washed with 1N HCl, saturatedNaHCO₃, and brine. The organic layer was dried, filtered, andconcentrated. This solid was dissolved in DMSO (5 mL) prior to theaddition of NaN₃ (326 mg). This was heated at 80° C. for 18 h. Aftercooling to 0° C., water was added and it was extracted with EtOAc. Theorganic layer was washed with brine, dried, filtered, and concentrated.Flash chromatography of the resulting residue gave(2-azido-5-benzyloxy-cyclohexyl)-carbamic acid tert-butyl ester (250mg). MS found: (M+H)⁺=347.2.

(179b) The above material (3 g) was dissolved in MeOH (25 mL) prior tothe addition of 10% Pd/C (2 g). A hydrogen balloon was added and thesolution was stirred for 1.0 h. The palladium was filtered and thesolution was concentrated. This material was dissolved in DMF prior tothe addition of 4-methylmorpholine (6.7 mL) and3-trifluoromethyl-benzoylamino)-acetic acid (3.3 g). After cooling to 0°C., BOP Reagent (7 g) was added. The resulting mixture was warmed to rtand was stirred overnight. EtOAc was added along with 1 N HCl solution(aq). The EtOAc layer was washed with 1 N HCl, NaHCO₃ solution (aq), andbrine. The EtOAc was dried (MgSO₄), filtered, and concentrated. Flashchromatography of the resulting residue gave{5-benzyloxy-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamicacid tert-butyl ester (8 g). MS found: (M+Na)⁺=550.4.

(179c) The above material (6 g) was dissolved in MeOH (50 mL) prior tothe addition of 10% Pd(OH)₂ (2.5 g). Hydrogen gas (50 psi) was added andthe solution was shaken overnight. The palladium was filtered and thesolution was concentrated (4.75 g). A portion (300 mg) of this materialwas dissolved in CH₂Cl₂ (5 mL) and cooled to 0° C. prior to the additionof Et₃N (0.26 mL) and methanesulfonyl chloride (0.08 mL). After 1 h, theCH₂Cl₂ was removed and EtOAc was added. This was washed with 1N HCl,saturated NaHCO₃, and brine. The organic layer was dried, filtered, andconcentrated. This solid was dissolved in DMSO (5 mL) prior to theaddition of NaN₃ (211 mg). This was heated at 80° C. for 18 h. Aftercooling to 0° C., water was added and it was extracted with EtOAc. Theorganic layer was washed with brine, dried, filtered, and concentrated.Flash chromatography of the resulting residue gave{5-azido-2-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl)-carbamicacid tert-butyl ester (140 mg). MS found: (M+H)⁺=485.5.

(179d) The above material (135 mg) was dissolved in MeOH (5 mL) prior tothe addition of 10% Pd/C (100 mg). A hydrogen balloon was added and thesolution was stirred 1 h. The palladium was filtered and the solutionwas concentrated. This was dissolved in MeOH (5 mL) prior to theaddition of 37% formaldehyde (106 mg) solution (aq). After 10 min,NaBH₃CN (49 mg) was added. The reaction was stirred for 2 h before thesolution was concentrated. EtOAc was added along with some water. Theorganic layer was dried, filtered, and concentrated. This was dissolvedin CH₂Cl₂ (5 mL) and TFA (5 mL). After 1 h, it was concentrated. Thiswas dissolved in THF (2.5 mL) prior to the addition of4-(methylthio)benzaldehyde (0.04 mL) and Hunig's base (0.1 mL). After 10min, NaHB(OAc)₃ was added. The reaction was stirred for 2 h before thesolution was filtered and concentrated. Reverse phase HPLC purification(gradient elution, water/acetonitrile/TFA) of the resulting residue gavethe title compound (35 mg). MS found: (M+H)⁺=523.4.

Example 180N-{[2-(4-Chloro-benzylamino)-4-dimethylamino-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

(180a) 4-Chlorobenzaldehyde (17 mg) was incorporated into Example 179 togive the title compound (2.5 mg). MS found: (M+H)⁺=511.3.

Example 181N-{[4-Dimethylamino-2-(4-methoxy-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

(181a) 4-(Methoxy)benzaldehyde (0.01 mL) was incorporated into Example179 to give the title compound (3.5 mg). MS found: (M+H)⁺=507.4.

Example 182N-{[4-Dimethylamino-2-(4-methyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamidetrifluoroacetate

(182a) 4-(Methyl)benzaldehyde (0.01 mL) was incorporated into Example179 to give the title compound (4.5 mg). MS found: (M+H)⁺=491.4.

Table 1 contains representative examples of the present invention. Eachof the following structural formulas are to be used in the indicatedexample (Ex) range paired with the given R¹ and R² substituent. TABLE 1

Ex 1-11

Ex 12

Ex 13-14

Ex 15-24, 144-146

Ex 25

Ex 26

Ex 27-31

Ex 32-34

Ex 35‥57; 61-125

Ex 58-60

Ex 67

Ex 68

Ex 127-130

Ex 131g, 132a, 133a

Ex 131-133

Ex 134

Ex 135

Ex 136

Ex 137

Ex 138

Ex 140

Ex 141

Ex 151

Ex 152

Ex 154-158

Ex 153, 172

Ex 159, 161

Ex 160

Ex 162

Ex 163

Ex 164-168

Ex 169-171

Ex 173

Ex 174

Ex 175-177

Ex 178

Ex 179-182 MS Ex R¹ R² [M + H] 1 4-chlorophenyl 3-trifluoromethylphenyl468.2 2 2,4- 3-trifluoromethylphenyl 462.3 dimethylphenyl 3 2,4,6-3-trifluoromethylphenyl 476.4 trimethylphenyl 4 4-benzyloxyphenyl3-trifluoromethylphenyl 540.4 5 2,4- 3-trifluoromethylphenyl 470.3difluorophenyl 6 2-chloro-4- 3-trifluoromethylphenyl 486.2 fluorophenyl7 4-fluoro-2- 3-trifluoromethylphenyl 520.2 trifluoromethyl phenyl 82,4- 3-trifluoromethylphenyl 502.1 dichlorophenyl 9 2-fluoro-6-3-trifluoromethylphenyl 520.2 trifluoromethyl phenyl 10 2-chloro-5-3-trifluoromethylphenyl 536.2 trifluoromethyl phenyl 11 1-naphthyl3-trifluoromethylphenyl 484.3 12 3-furyl 3-trifluoromethylphenyl 504.313 2,4- 3-trifluoromethylphenyl 476.3 dimethylphenyl 14 4-chlorophenyl3-trifluoromethylphenyl 482.3 15 2,4- 3-trifluoromethylphenyl 462.4dimethylphenyl 16 4-chlorophenyl 3-trifluoromethylphenyl 468.3 174-nitrophenyl 3-trifluoromethylphenyl 479.3 18 4-isopropylphenyl3-trifluoromethylphenyl 476.3 19 4-trifluoromethyl3-trifluoromethylphenyl 502.3 phenyl 20 4- 3-trifluoromethylphenyl 518.2trifluoromethoxy- phenyl 21 4-phenoxyphenyl 3-trifluoromethylphenyl526.2 22 1-naphthyl 3-trifluoromethylphenyl 484.3 23 2-naphthyl3-trifluoromethylphenyl 484.3 24 3-indolyl 3-trifluoromethylphenyl 473.325 4-chlorophenyl 3-trifluoromethylphenyl 482.2 26 3-furyl3-trifluoromethylphenyl 504.3 27 4-chlorophenyl 3-trifluoromethylphenyl468.2 28 4- 3-trifluoromethylphenyl 480.2 methylthiophenyl 294-methylsulfonyl 3-trifluoromethylphenyl 512.1 phenyl 30 4-iodophenyl3-trifluoromethylphenyl 431.0 31 4-aminosulfonyl 3-trifluoromethylphenyl535.1 phenyl M + Na 32 4-chlorophenyl 3-trifluoromethylphenyl 454.1 332,4- 3-trifluoromethylphenyl 448.2 dimethylphenyl 34 4-methylphenyl3-trifluoromethylphenyl 434.1 35 4-chlorophenyl 3-trifluoromethylphenyl482.2 36 4-methylphenyl 3-trifluoromethylphenyl 484.2 M + Na 374-fluorophenyl 3-trifluoromethylphenyl 466.2 38 phenyl3-trifluoromethylphenyl 448.2 39 4-bromophenyl 3-trifluoromethylphenyl528.1 40 4-phenoxyphenyl 3-trifluoromethylphenyl 540.2 414-trifluoromethyl 3-trifluoromethylphenyl 516.2 phenyl 425-benzotriazolyl 3-trifluoromethylphenyl 489.2 43 4-iodophenyl3-trifluoromethylphenyl 574.2 44 4-cyanophenyl 3-trifluoromethylphenyl473.3 45 4- 3-trifluoromethylphenyl 532.2 trifluoromethoxy phenyl 464-formylphenyl 3-trifluoromethylphenyl 476.3 47 4-carbomethoxy3-trifluoromethylphenyl 506.2 phenyl 48 4-nitrophenyl3-trifluoromethylphenyl 493.2 49 4-aminophenyl 3-trifluoromethylphenyl463.2 50 4-methoxyphenyl 3-trifluoromethylphenyl 478.3 51 4-3-trifluoromethylphenyl 494.2 methylthiophenyl 52 4-methylsulfonyl3-trifluoromethylphenyl 526.2 phenyl 53 4-aminosulfonyl3-trifluoromethylphenyl 527.2 phenyl 54 4-isopropylphenyl3-trifluoromethylphenyl 490.3 55 4- 3-trifluoromethylphenyl 556.2phenylthiophenyl 56 N,N- 3-trifluoromethylphenyl 583.3 diethylsulfamoylphenyl 57 4-trifluoromethyl 3-trifluoromethylphenyl 548.2 thiophenyl 584-chlorophenyl 3-trifluoromethylphenyl 550.1 59 3,4-3-trifluoromethylphenyl 420.1 dimethylphenyl 60 4-methylphenyl3-trifluoromethylphenyl 406.1 61 4-aminosulfonyl 2-amino-5-iodophenyl622.2 phenyl M + Na 62 4-aminosulfonyl 2-amino-5-chlorophenyl 530.3phenyl M + Na 63 4-aminosulfonyl 3-chlorophenyl 515.2 phenyl 644-aminosulfonyl 3-trifluoromethoxyphenyl 543.1 phenyl 65 4-aminosulfonyl2-(t-butoxycarbonyl)amino- 664.3 phenyl 5-trifluoromethylphenyl M + Na66 4-aminosulfonyl 2-amino-5- 564.2 phenyl trifluoromethylphenyl M + Na67 4-aminosulfonyl 2-trifluoromethylphenyl 564.3 phenyl M + Na 684-aminosulfonyl 3-chlorophenyl 530.1 phenyl 69 4-aminosulfonyl2-(ethylcarbonyl)amino-5- 670.9 phenyl iodophenyl M − H 704-aminosulfonyl 2-(methylcarbonyl)amino-5- 656.9 phenyl iodophenyl M − H71 4-aminosulfonyl N-methyl-2-(t- 678.2 phenyl butoxycarbonyl)amino-5-M + Na trifluoromethylphenyl 72 4-aminosulfonyl2-(ethylcarbonyl)amino-5- 636.1 phenyl trifluoromethylphenyl M + Na 734-aminosulfonyl 2-(benzylamino)-5- 654.2 phenyl trifluoromethylphenylM + Na 74 4-aminosulfonyl 2-(ethylamino)-5- 592.1 phenyltrifluoromethylphenyl M + Na 75 4-aminosulfonyl 2-(methylamino)-5- 578.2phenyl trifluoromethylphenyl M + Na 76 4-aminosulfonyl2-amino-5-bromophenyl 554.1 phenyl M + H 77 4-aminosulfonyl2-(t-butoxycarbonyl)amino- 680.2 phenyl 5-trifluoromethoxyphenyl M + Na78 4-aminosulfonyl 2-amino-5- 580.1 phenyl trifluoromethoxyphenyl M + Na79 4-aminosulfonyl 2-(allylamino)-5- 604.1 phenyl trifluoromethylphenylM + Na 80 4-aminosulfonyl 2-((2-methyl-2- 618.1 phenylpropenyl)amino)-5- M + Na trifluoromethylphenyl 81 4-aminosulfonyl 2-618.2 phenyl (cyclopropylmethylene) M + Na amino-5-trifluoromethylphenyl 82 4-aminosulfonyl 2-(butylamino)-5- 620.1 phenyltrifluoromethylphenyl M + Na 83 4-aminosulfonyl 2-(propylamino)-5- 606.2phenyl trifluoromethylphenyl M + Na 84 4-aminosulfonyl 2-((2-methyl-2-620.2 phenyl propyl)amino)-5- M + Na trifluoromethylphenyl 854-aminosulfonyl 2-(aminocarbonyl)amino-5- 665.1 phenyl iodophenyl M + Na86 4-aminosulfonyl 2-acetylamino-5-iodophenyl 642.1 phenyl M + H 874-aminosulfonyl 2-(methylamino)-5- 614.1 phenyl iodophenyl M + H 884-aminosulfonyl 2-(ethylamino)-5-iodophenyl 628.1 phenyl M + H 894-aminosulfonyl 2-trifluoroacetylamino-5- 696.1 phenyl lodophenyl M + H90 4-aminosulfonyl 2-amino-5-nitrophenyl 519.1 phenyl M + H 914-aminosulfonyl 2-(iso- 708.1 phenyl propoxycarbonyl)amino-5- M + Naiodophenyl 92 4-aminosulfonyl 2-(tert- 722.1 phenylbutoxycarbonyl)amino-5- M + Na iodophenyl 93 4-aminosulfonyl 2-amino-3,5-dinitrophenyl 632.0 phenyl M + H 94 4-aminosulfonyl 2- 649.2 phenyl(isopropylaminocarbonyl) M + Na amino-5- trifluoromethylphenyl 954-aminosulfonyl 2- 652.2 phenyl (cyclohexylcarbonyl)amino- M + H5-trifluoromethylphenyl 96 4-aminosulfonyl 2- 652.2 phenyl(cyclopentylmethylene- M + H carbonyl)amino-5- trifluoromethylphenyl 974-methylsulfonyl 2- 651.2 phenyl (cyclohexylcarbonyl)amino- M + H5-trifluoromethylphenyl 98 4-(methylthio) 2- 619.3 phenyl(cyclohexylcarbonyl)amino- M + H 5-trifluoromethylphenyl 994-(methylthio) 2- 594.3 phenyl (isopropylaminocarbonyl) M + H amino-5-trifluoromethylphenyl 100 4- 2- 626.2 (methylsulfonyl)(isopropylaminocarbonyl) M + H phenyl amino-5- trifluoromethylphenyl 1014-aminosulfonyl 2-(methylsulfonyl)amino- 620.1 phenyl5-trifluoromethylphenyl M + H 102 4-aminosulfonyl2-(aminocarbonyl)amino-5- 585.2 phenyl trifluoromethylphenyl M + H 1044- 2-(allyl)amino-5- 581.3 (methylsulfonyl) trifluoromethylphenyl M + Hphenyl 105 4-(methylthio) 2-(allyl)amino-5- 549.3 phenyltrifluoromethylphenyl M + H 106 4- 2-(2-methyl-2- 595.2 (methylsulfonyl)propenyl)amino-5- M + H phenyl trifluoromethylphenyl 107 4-(methylthio)2-(2-methyl-2- 563.3 phenyl propenyl)amino-5- M + Htrifluoromethylphenyl 108 4- 2-(propyl)amino-5- 583.3 (methylsulfonyl)trifluoromethylphenyl M + H phenyl 109 4-(methylthio) 2-(propyl)amino-5-551.3 phenyl trifluoromethylphenyl M + H 110 4-2-(2-methylpropyl)amino-5- 597.3 (methylsulfonyl) trifluoromethylphenylM + H phenyl 111 4-(methylthio) 2-(2-methylpropyl)amino-5- 565.3 phenyltrifluoromethylphenyl M + H 112 4- 2-(butyl)amino-5- 597.2(methylsulfonyl) trifluoromethylphenyl M + H phenyl 113 4-(methylthio)2-(butyl)amino-5- 565.3 phenyl trifluoromethylphenyl M + H 1144-(methylthio) 2- 602.4 phenyl (ethylaminocarbonyl)amino- M + Na5-trifluoromethylphenyl 115 4-(methylthio) 2- 592.3 phenyl(allylaminocarbonyl)amino- M + H 5-trifluoromethylphenyl 1174-(methylthio) 2-(iso- 608.3 phenyl butylaminocarbonyl)amino- M + H5-trifluoromethylphenyl 118 4-(methylthio) 2- 620.3 phenyl(cyclopentylaminocarbonyl) M + H amino-5- trifluoromethylphenyl 1194-(methylthio) 2-(tert- 609.3 phenyl butoxycarbonyl)amino-5- M + Htrifluoromethylphenyl 120 4-(methylthio) 2-(iso- 595.3 phenylpropoxycarbonyl)amino-5- M + H trifluoromethylphenyl 121 4-(methylthio)2-(Ethoxycarbonyl)amino-5- 581.3 phenyl trifluoromethylphenyl M + H 1234-(methylthio) 2- 606.5 phenyl (pyrrolidinylcarbonyl)amino- M + H5-trifluoromethylphenyl 124 4-(methylthio) 2- 644.6 phenyl(morpholinylcarbonyl)amino- M + Na 5-trifluoromethylphenyl 1254-(methylthio) 2- 592.5 phenyl (azetidinylcarbonyl)amino- M + H5-trifluoromethylphenyl 127 4-(methylthio) 2- 594.5 phenyl(pyrrolidinylcarbonyl)amino- M + H 5-trifluoromethylphenyl 1294-(methylthio) 2- 580.5 phenyl (azetidinylcarbonyl)amino- M + H5-trifluoromethylphenyl 130 4-(methoxy)phenyl 2- 564.4(azetidinylcarbonyl)amino- M + H 5-trifluoromethylphenyl 1314-(methylthio) 2-amino-5- 524.3 phenyl trifluoromethylphenyl M + H 131g4-(methylthio) 2-(t-butoxycarbonyl)amino- 758.1 phenyl5-trifluoromethylphenyl M + H 132 4-(methylthio) 3-trifluoromethylphenyl509.2 phenyl M + H 132a 4-(methylthio) 3-trifluoromethylphenyl 643.2phenyl M + H 133 4- 3-trifluoromethylphenyl 541.2 (methylsulfonyl) M + Hphenyl 133a 4- 3-trifluoromethylphenyl 675.2 (methylsulfonyl) M + Hphenyl 134 4-(methylthio) 2-amino-5- 566.1 phenyl trifluoromethylphenylM + H 135 4-(methylthio) 2-amino-5- 581.0 phenyl trifluoromethylphenylM + H 136 4-(methylthio) 3-trifluoromethylphenyl 509.2 phenyl M + H 1374-(methylthio) 3-trifluoromethylphenyl 551.0 phenyl M + H 1384-(methylthio) 2-amino-5- 524.3 phenyl trifluoromethylphenyl M + H 1404-(methylthio) 3-trifluoromethylphenyl 551.2 phenyl M + H 1414-(methylthio) 3-trifluoromethylphenyl 509.1 phenyl M + H 1444-(methylthio) 2-(iso-propyl)amino-5- 537.2 phenyl trifluoromethylphenylM + H 145 4-(methylthio) 2-(i- 580.1 phenyl propylaminocarbonyl)amino-M + H 5-trifluoromethylphenyl 146 4-(methylthio) 2- 608 phenyl(morpholinylcarbonyl)amino- M + H 5-trifluoromethylphenyl 1514-(methylthio) 2-amino-5- 538.5 phenyl trifluoromethylphenyl M + H 1524-(methylthio) 2-amino-5- 538.5 phenyl trifluoromethylphenyl M + H 1534-(methylthio) 2-amino-5- 524.4 phenyl trifluoromethylphenyl M + H 1544-chlorophenyl 3-trifluoromethylphenyl 469.3 M + H 155 4-(methylthio)3-trifluoromethylphenyl 481.2 phenyl M + H 156 4-chlorophenyl 2-amino-5-484.4 trifluoromethylphenyl M + H 157 4-(methylthio) 2-amino-5- 496.5phenyl trifluoromethylphenyl M + H 158 4- 2-amino-5- 510.5(ethylthio)phenyl trifluoromethylphenyl M + H 159 4-(methylthio)3-trifluoromethylphenyl 493.3 phenyl M + H 160 4-(methylthio)3-trifluoromethylphenyl 631.3 phenyl M + H 161 4-(methylthio) 2-amino-5-510.3 phenyl trifluoromethylphenyl M + H 162 4-(methylthio)3-trifluoromethylphenyl 551.4 phenyl M + H 163 4-(methylthio) 2-amino-5-552.5 phenyl trifluoromethylphenyl M + H 164 4-(methylthio)2-(cyclohexyl)amino-5- 620.6 phenyl trifluoromethylphenyl M + H 1654-(methylthio) 2-(iso-propyl)amino-5- 580.5 phenyl trifluoromethylphenylM + H 166 4-(methylthio) 2- 635.6 phenyl (pyrrolidinylcarbonyl)amino-M + H 5-trifluoromethylphenyl 167 4-(methylthio) 2- 595.6 phenyl(methylaminocarbonyl)amino- M + H 5-trifluoromethylphenyl 1684-(methylthio) 3-amino-5- 538.5 phenyl trifluoromethylphenyl M + H 1694-aminosulfonyl 3-trifluoromethylphenyl 528.3 phenyl M + H 1704-methylsulfonyl 3-trifluoromethylphenyl 527.0 phenyl M + H 1714-(methylthio) 2-amino-5- 510.3 phenyl trifluoromethylphenyl M + H 1724-(methylthio) 3-trifluoromethylphenyl 509.3 phenyl M + H 1734-(methylthio) 3-trifluoromethylphenyl 559.3 phenyl M + H 1744-(methylthio) 2-amino-5- 566.5 phenyl trifluoromethylphenyl M + H 1754-(methylthio) 2-(cyclohexyl)amino-5- 634.6 phenyl trifluoromethylphenylM + H 176 4-(methylthio) 2-(iso-propyl)amino-5- 594.4 phenyltrifluoromethylphenyl M + H 177 4-(methylthio) 3-amino-5- 552.4 phenyltrifluoromethylphenyl M + H 178 4-aminosulfonyl 3-trifluoromethylphenyl528.1 phenyl M + H 179 4- 3-trifluoromethylphenyl 523.4(methylthio)phenyl M + H 180 4-(chloro)phenyl 3-trifluoromethylphenyl511.3 M + H 181 4-(methoxy)phenyl 3-trifluoromethylphenyl 507.4 M + H182 4-(methyl)phenyl 3-trifluoromethylphenyl 491.4 M + H

Table 2 contains additional examples of the present invention. Each ofthe following structural formulas (A to GG) are to be matched with eachR¹ and each R² independently. TABLE 2

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

AA

BB

CC

DD

EE

FF

GG R¹ 4 4-ethenylphenyl 5 4-ethylphenyl 6 4-ethynylphenyl 74-isopropylphenyl 8 4-phenoxyphenyl 9 4-trifluoromethylphenyl 104-cyanophenyl 11 4-nitrophenyl 12 4-methylphenyl 13 4-methylthiophenyl14 4-methylsulfonylphenyl 15 4-methoxyphenyl 16 2,4-dimethylphenyl 172,4,6-trimethylphenyl 18 3,4-dimethylphenyl 19 4-fluorophenyl 201-naphthyl 21 2-naphthyl 22 4-chloro-3-methylphenyl 232,4-dichlorophenyl 24 2,5-dimethylphenyl 25 2-chloro-5-trifluoromethylphenyl 26 4-chloro-2-methylphenyl 274-chloro-2-fluorophenyl 28 2,4-difluorophenyl 29 2-chloro-4-trifluoromethylphenyl 30 2-fluoro-6- trifluoromethylphenyl 312-chloro-5- trifluoromethylphenyl 32 4-fluoro-2- trifluoromethylphenyl33 4-hydroxyphenyl 34 3-indolyl 35 3,5-dimethyl-4-isoxazole 363,5-dimethyl-1-phenyl-4- pyrazolyl 37 3-amino-4-methylphenyl 383-amino-4-chlorophenyl 39 3-amino-4-methoxyphenyl R² 13-trifluoromethylphenyl 2 3-bromophenyl 3 3,5-dibromophenyl 43-chlorophenyl 5 3-trifluoromethoxyphenyl 6 3-trifluorothiophenyl 73-cyanophenyl 8 3-iodophenyl 9 3-formylphenyl 10 3-nitrophenyl 115-tert-butyl-2-furanyl 12 3-methylsulfonylphenyl 132-amino-5-chlorophenyl 14 2-amino-5-bromophenyl 15 2-amino-5-iodophenyl16 2-amino-5-trifluoromethylphenyl 17 2-amino-5-fluorophenyl 182-amino-5-trifluoromethoxyphenyl 19 2-amino-5-cyanophenyl 202-amino-5-formylphenyl 21 2-(methylamino)-5-chlorophenyl 222-(methylamino)-5-bromophenyl 23 2-(methylamino)-5-iodophenyl 242-(methylamino)-5-fluorophenyl 252-(methylamino)-5-trifluoromethylphenyl 262-(methylamino)-5-trifluoromethoxyphenyl 272-(methylamino)-5-cyanophenyl 28 2-(ethylamino)-5-chlorophenyl 292-(ethylamino)-5-bromophenyl 30 2-(ethylamino)-5-lodophenyl 312-(methylamino)-5-fluorophenyl 32 2-(ethylamino)-5-trifluoromethylphenyl33 2-(methylamino)-5-trifluoromethoxyphenyl 342-(ethylamino)-5-cyanophenyl 35 2-(aminocarbonyl)amino-5-chlorophenyl 362-(aminocarbonyl)amino-5-bromophenyl 372-(aminocarbonyl)amino-5-iodophenyl 382-(aminocarbonyl)amino-5-fluorophenyl 392-(aminocarbonyl)amino-5-trifluoromethylphenyl 402-(aminocarbonyl)amino-5-trifluoromethyloxyphenyl 412-(aminocarbonyl)amino-5-cyanophenyl 422-[(methylamino)carbonyl)]amino-5-chlorophenyl 432-[(methylamino)carbonyl)]amino-5-bromophenyl 442-[(methylamino)carbonyl)]amino-5-iodophenyl 452-[(methylamino)carbonyl)]amino-5-fluorophenyl 462-[(methylaxnino)carbonyl)]amino-5- trifluoromethylphenyl 472-[(methylamino)carbonyl)]amino-5- trifluoromethoxyphenyl 482-[(methylamino)carbonyl)]amino-5-cyanophenyl R⁴ 1 H 2 methyl 3 ethyl 4propyl 5 i-propyl 6 Butyl 7 1-butyl 8 t-butyl 9 Pentyl 10 Hexyl 11C(O)methyl 12 C(O)H 13 C(O)methyl 14 C(O)ethyl 15 C(O)propyl 16C(O)i-propyl 17 C(O)butyl 18 C(O)i-butyl 19 C(O)t-butyl 20 C(O)pentyl 21C(O)cyclopropyl R^(5a) 1 H 2 methyl 3 ethyl 4 propyl 5 1-propyl 6 Butyl7 1-butyl 8 Pentyl 9 Hexyl 10 cyclopropyl 11 cyclobutyl

Table 3 contains additional examples of the present invention. Each ofthe following structural formulas (A to W) are to be matched with eachR¹ and each R² independently. TABLE 3

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y R¹ 1 4-chlorophenyl 2 4-bromophenyl 3 4-iodophenyl 4 4-ethenylphenyl 54-ethylphenyl 6 4-ethynylphenyl 7 4-isopropylphenyl 8 4-phenoxyphenyl 94-trifluoromethylphenyl 10 4-cyanophenyl 11 4-nitrophenyl 124-methylphenyl 13 4-methylthiophenyl 14 4-methylsulfonylphenyl 154-amninosulfonylphenyl 16 4-(methylamino)sulfonylphenyl 17 4-(dimethylamino)sulfonylphenyl 18 4-formylphenyl 194-(methoxycarbonyl)phenyl 20 4-trifluoromethoxyphenyl 21 4-aminophenyl22 4-methylthiophenyl 23 4-(aminocarbonyl)phenyl 24 4-aminophenyl 25phenyl 26 4-propylphenyl 27 4-difluoromethylphenyl 284-(phenylthio)phenyl 29 4-ethylthiophenyl 30 4-ethylsulfonylphenyl R² 13-trifluoromethylphenyl 2 3-bromophenyl 3 3,5-dibromophenyl 43-chlorophenyl 5 3-trifluoromethoxyphenyl 6 3-trifluoromethylthiophenyl7 3-cyanophenyl 8 3-iodophenyl 9 3-formylphenyl 10 3-nitrophenyl 115-tert-butyl-2-furanyl 12 3-methylsulfonylphenyl 132-amino-5-chlorophenyl 14 2-amino-5-bromophenyl 15 2-amino-5-iodophenyl16 2-amino-5-trifluoromethylphenyl 17 2-amino-5-fluorophenyl 182-amino-5-trifluoromethoxyphenyl 19 2-amino-5-cyanophenyl 202-amino-5-formylphenyl 21 2-(methylamino)-5-chlorophenyl 222-(methylamino)-5-bromophenyl 23 2-(methylamino)-5-iodophenyl 242-(methylamino)-5-fluorophenyl 252-(methylamino)-5-trifluoromethylphenyl 262-(methylamino)-5-trifluoromethoxyphenyl 272-(methylamino)-5-cyanophenyl 28 2-(ethylamino)-5-chlorophenyl 292-(ethylamino)-5-bromophenyl 30 2-(ethylamino)-5-iodophenyl 312-(methylamino)-5-fluorophenyl 32 2-(ethylamino)-5-trifluoromethylphenyl33 2-(methylamino)-5-trifluoromethoxyphenyl 342-(ethylamino)-5-cyanophenyl 35 2-(aminocarbonyl)amino-5-chlorophenyl 362-(aminocarbonyl)amino-5-bromophenyl 372-(aminocarbonyl)amino-5-iodophenyl 382-(aminocarbonyl)amino-5-fluorophenyl 392-(aminocarbonyl)amino-5-trifluoromethylphenyl 402-(aminocarbonyl)amino-5-trifluoromethyloxyphenyl 412-(aminocarbonyl)amino-5-cyanophenyl 422-[(methylamino)carbonyl)]amino-5-chlorophenyl 432-[(methylamino)carbonyl)]amino-5-bromophenyl 442-[(methylamino)carbonyl)]amino-5-iodophenyl 452-[(methylamino)carbonyl)]amino-5-fluorophenyl 462-[(methylamino)carbonyl)]amino-5- trifluoromethylphenyl 472-[(methylamino)carbonyl)]amino-5- trifluoromethoxyphenyl 482-[(methylamino)carbonyl)]amino-5-cyanophenyl R⁴ 1 H 2 methyl 3 ethyl 4propyl 5 i-propyl 6 Butyl 7 1-butyl 8 t-butyl 9 Pentyl 10 Hexyl 11C(O)methyl 12 C(O)H 13 C(O)methyl 14 C(O)ethyl 15 C(O)propyl 16C(O)i-propyl 17 C(O)butyl 18 C(O)i-butyl 19 C(O)t-butyl 20 C(O)pentyl 21C(O)cyclopropyl

Utility

Compounds of formula I are shown to be modulators of chemokine receptoractivity using assays know by those skilled in the art. In this section,we describe these assays and give their literature reference. Bydisplaying activity in these assays of MCP-1 antagonism, compounds offormula I are expected to be useful in the treatment of human diseasesassociated with chemokines and their cognate receptors. The definitionof activity in these assays is a compound demonstrating an IC₅₀ of 20 μMor lower in concentration when measured in a particular assay.

Antagonism of MCP-1 Binding to Human PBMC (Yoshimura et al., J. Immunol.1990, 145, 292)

Compounds of the present invention have activity in the antagonism ofMCP-1 binding to human PBMC (human peripheral blood mononuclear cells)described here.

Millipore filter plates (#MABVN1250) are treated with 100 μl of bindingbuffer (0.5% bovine serum albumin, 20 mM HEPES buffer and 5 mM magnesiumchloride in RPMI 1640 media) for thirty minutes at room temperature. Tomeasure binding, 50 μl of binding buffer, with or without a knownconcentration compound, is combined with 50 μl of ¹²⁵-I labeled humanMCP-1 (to give a final concentration of 150 pM radioligand) and 50 μl ofbinding buffer containing 5×10⁵ cells. Cells used for such bindingassays can include human peripheral blood mononuclear cells isolated byFicoll-Hypaque gradient centrifugation, human monocytes (Weiner et al.,J. Immunol. Methods. 1980, 36, 89), or the THP-1 cell line whichexpresses the endogenous receptor. The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and the plates washedthree times with binding buffer containing 0.5M NaCl. The plastic skirtis removed from the plate, the plate allowed to air dry, the wellspunched out and counted. The percent inhibition of binding is calculatedusing the total counts obtained in the absence of any competing compoundand the background binding determined by addition of 100 nM MCP-1 inplace of the test compound.

Antagonism of MCP-1-Induced Calcium Influx (Sullivan, et al. MethodsMol. Biol., 114, 125-133 (1999)

Compounds of the present invention have activity in the antagonism ofMCP-1-induced calcium influx assay described here.

Calcium mobilization is measured using the fluorescent Ca²⁺ indicatordye, Fluo-3. Cells are incubated at 8×105 cells/ml in phosphate-bufferedsaline containing 0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mMglucose, 1% fetal bovine serum, 4 μM Fluo-3 AM and 2.5 mM probenecid for60 minutes at 37° C. Cells used for such calcium assays can includehuman monocytes isolated as described by Weiner et al., J. Immunol.Methods, 36, 89-97 (1980) or cell lines which expresses the endogenousCCR2 receptor such as THP-1 and MonoMac-6. The cells are then washedthree times in phosphate-buffered saline containing 0.1% bovine serumalbumin, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid. The cells areresuspended in phosphate-buffered saline containing 0.5% bovine serumalbumin, 20 mM HEPES and 2.5 mM probenecid at a final concentration of2-4×10⁶ cells/ml. Cells are plated into 96-well, black-wall microplates(100 μl/well) and the plates centrifuged at 200×g for 5 minutes. Variousconcentrations of compound are added to the wells (50 μl/well) and after5 minutes, 50 μl/well of MCP-1 is added to give a final concentration of10 nM. Calcium mobilization is detected by using a fluorescent-imagingplate reader. The cell monolayer is excited with an argon laser (488 nM)and cell-associated fluorescence measured for 3 minutes, (every secondfor the first 90 seconds and every 10 seconds for the next 90 seconds).Data are generated as arbitrary fluorescence units and the change influorescence for each well determined as the maximum-minimumdifferential. Compound-dependent inhibition is calculated relative tothe response of MCP-1 alone.

Antagonism of MCP-1-induced Human PBMC Chemotaxis (Bacon et al., Brit.J. Pharmacol. 1988, 95, 966)

Compounds of the present invention have activity in the antagonism ofMCP-1-induced human PBMC chemotaxis assay described here.

Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics MPC 96 wellplate, and Neuroprobe polyvinylpyrrolidone-free polycarbonate PFD58-micron filters are warmed in a 37° C. incubator. Human PeripheralBlood Mononuclear Cells (PBMCs) (Boyum et al., Scand. J. Clin. LabInvest. Suppl. 1968, 97, 31), freshly isolated via the standard ficolldensity separation method, are suspended in DMEM at 1×10⁷ c/ml andwarmed at 37° C. A 60 nM solution of human MCP-1 is also warmed at 37°C. Dilutions of test compounds are made up at 2× the concentrationneeded in DMEM. The PBMC suspension and the 60 nm MCP-1 solution aremixed 1:1 in polypropylene tubes with prewarmed DMEM with or without adilution of the test compounds. These mixtures are warmed in a 37° C.tube warmer. To start the assay, add the MCP-1/compound mixture into thewells of the Polyfiltronics MPC 96 well plate that has been placed intothe bottom part of the Neuroprobe chemotaxis chamber. The approximatevolume is 400 μl to each well and there should be a positive meniscusafter dispensing. The 8 micron filter is placed gently on top of the 96well plate, a rubber gasket is attached to the bottom of the upperchamber, and the chamber is assembled. A 200 μl volume of the cellsuspension/compound mixture is added to the appropriate wells of theupper chamber. The upper chamber is covered with a plate sealer, and theassembled unit is placed in a 37° C. incubator for 45 minutes. Afterincubation, the plate sealer is removed and all the remaining cellsuspension is aspirated off. The chamber is disassembled and the filtergently removed. While holding the filter at a 90 degree angle,unmigrated cells are washed away using a gentle stream of phosphatebuffered saline and the top of the filter wiped with the tip of a rubbersqueegee. Repeat this wash twice more. The filter is air dried and thenimmersed completely in Wright Geimsa stain for 45 seconds. The filter isthen washed by soaking in distilled water for 7 minutes, and then a 15second additional wash in fresh distilled water. The filter is again airdried. Migrated cells on the filter are quantified by visual microscopy.Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

Preferably, the compounds of the present invention are used to treat orprevent disorders selected from rheumatoid arthritis, osteoarthritis,septic shock, atherosclerosis, aneurism, fever, cardiovascular effects,haemodynamic shock, sepsis syndrom, post ischemic reperfusion injury,malaria, Crohn's disease, inflammatory bowel diseases, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, autoimmune diseases, skininflammatory diseases, multiple sclerosis, radiation damage, hyperoxicalveolar injury, HIV, HIV dementia, non-insulin dependent diabetesmelitus, asthma, allergic rhinitis, atopic dermatitis, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, cystic fibrosis, Churg-Strauss syndrome, lymphoma,Hodgkin's disease, colonic carcinoma, Felty's syndrome, sarcoidosis,uveitis, Alzheimer, Glomerulonephritis, and systemic lupuserythematosus.

More preferably, the compounds are used to treat or prevent inflammatorydisorders selected from from rheumatoid arthritis, osteoarthritis,atherosclerosis, aneurism, fever, cardiovascular effects, Crohn'sdisease, inflammatory bowel diseases, psoriasis, congestive heartfailure, multiple sclerosis, autoimmune diseases, skin inflammatorydiseases.

Even more preferably, the compounds are used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, Crohn's disease, inflammatory boweldiseases, and multiple sclerosis.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) integrin antagonists such as those for selectins, ICAMs and VLA-4;(b) steroids such as beclomethasone, methylprednisolone, betamethasone,prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressantssuch as cyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102, 203), leukotriene biosynthesisinhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatoryagents (NSAIDs) such as propionic acid derivatives (alminoprofen,benxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, andtioxaprofen), acetic acid derivatives (indomethacin, acemetacin,alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac,tolmetin, zidometacin, and zomepirac), fenamic acid derivatives(flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid andtolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal andflufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones(apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone,phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitorsof phosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (l) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient.

Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Dosage forms(pharmaceutical compositions) suitable for administration may containfrom about 1 milligram to about 100 milligrams of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. In general, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Representative useful pharmaceutical dosage-formsfor administration of the compounds of this invention can be illustratedas follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin. Where the compoundsof this invention are combined with other anticoagulant agents, forexample, a daily dosage may be about 0.1 to 100 milligrams of thecompound of Formula I and about 1 to 7.5 milligrams of the secondanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the compounds of this invention generally may be present in anamount of about 5 to 10 milligrams per dosage unit, and the secondanti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination. Particularly when provided as asingle dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a lowviscosity grade of hydroxypropylmethylcellulose (HPMC) or other appropriate materials as known in theart, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the cycloalkyl group is saturated or partially unsaturated; or a heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or partially unsaturated, the heterocycle containing a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionally containing a —C(O)—; ring B being substituted with 0-2 R⁵; Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and —SO₂NH—; R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, C₁₋₄ cycloalkyl, CF₃, or alternatively, R^(1a) and R^(1b) are taken together to from ═O; R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R⁷; R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)SR^(4d), (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)rC(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e); R^(4a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-4 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e); R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e); R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d), —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R^(4d), at each occurrence, is selected from methyl, CF₃, C₁₋₆ alkyl substituted with 0-3 R^(4e), C³⁻⁸ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e); R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4i), —C(O)NR^(4h)R^(4h), —OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4j), and (CH₂)_(r)phenyl; R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(4h), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic; R^(4i)i, at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue; R^(4j), at each occurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue; R⁵, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂ NR^(5a)R^(5a), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(5c); R^(5a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e); R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e); R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(=NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(=NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and (CH₂)_(r)phenyl substituted with 0-3 R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)SC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a), (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f), (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(6e); alternatively, two R⁶ on adjacent atoms on R¹ may join to form a cyclic acetal; R^(6a), at each occurrence, is selected from H, methyl substituted with 0-1 R^(6g)g, C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e); R^(6b), at each occurrence, is selected from H; C₁₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e); R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e); R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d), —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(7b), (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a), (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a), (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a), (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f), (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a), (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e); alternatively, two R⁷ on adjacent atoms on R² may join to form a cyclic acetal; R^(7a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e); R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e); R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e); R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d), —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(6e); R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; R⁹ is selected from, H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and (CH₂)—R¹; R¹⁰ and R^(10a) are independently selected from H, and C₁₋₄alkyl substituted with 0-1 R^(10b), alternatively, R¹⁰ and R^(10a) can join to form a C₃₋₆ cycloalkyl; R^(10b), at each occurrence, is independently selected from —OH, —SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(11d), (CHR)_(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b), (CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b), (CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a), (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11a), at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11b), at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11d), at each occurrence, is independently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R¹¹e, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b), (CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b), (CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a), (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12a), at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12b), at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12d), at each occurrence, is independently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂₁ (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl; R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹³, at each occurrence, is independently selected from methyl, C₂₋₄ alkyl substituted with 0-1 R^(13b); R^(13b) is selected from —OH, —SH, —NR¹³CR^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; n is selected from 1 and 2; m is selected from 0 and 1; p, at each occurrence, is independently selected from 0, 1, and 2; q, at each occurrence, is independently selected from 1, 2, 3, and 4; r, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; s, at each occurrence, is independently selected from 0 and 1; and t, at each occurrence, is independently selected from 2, 3, and
 4. 2. A compound claim 1, wherein ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the cycloalkyl group is saturated or partially unsaturated; or a heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or partially unsaturated, the heterocycle containing a heteroatom selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R⁴)—, the heterocycle optionally containing a —C(O)—; ring B being substituted with 0-2 R⁵; Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and —SO₂NH—; R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, C₁₋₄ cycloalkyl, CF₃, or alternatively, R^(1a) and R^(1b) are taken together to from ═O; R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁶ and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R⁶; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁷ and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R⁷; R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CHR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e), and a (CHR)_(r)-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e); R^(4a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-4 R^(4e); R^(4b), at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(4e); R^(4c) is independently selected from —C(O)R^(4b), —C(O)OR^(4d), —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R^(4d), at each occurrence, is selected from methyl, CF₃, C₁₋₆ alkyl substituted with 0-3 R^(4e), C₃₋₈ alkenyl substituted with 0-3 R^(4e), C₃₋₈ alkynyl substituted with 0-3 R^(4e), and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e); R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4f)R^(4f), —C(O)R^(4i), —C(O)OR^(4j), —C(O)NR^(4h)R^(4h), —OC(O)NR^(4h)R^(4h), —NR^(4h)C(O)NR^(4h)R^(4h), —NR^(4h)C(O)OR^(4j), and (CH₂)_(r)phenyl; R^(4f), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(4h), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic; R^(4i), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue; R^(4i), at each occurrence, is selected from CF₃, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue; R⁵, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)OC(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), (CRR)_(r)NR^(5a)S(O)₂ NR^(5a)R^(5a), C₁₋₆ haloalkyl, a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5c), and a (CRR)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(5c); R^(5a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e); R^(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted with 0-3 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(5e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e); R^(5c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(5f)R^(5f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)C(O)R^(5b), (CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)C(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)_(p)R^(5b), (CH₂)_(r)NHC(═NR^(5f))NR^(5f)R^(5f), (CH₂)_(r)S(O)₂NR^(5f)R^(5f), (CH₂)_(r)NR^(5f)S(O)₂R^(5b), and (CH₂)_(r)phenyl substituted with 0-3 R^(5e); R^(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e); R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with R^(5e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(5e); R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(6d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)NR^(6a)R^(6a), (CR′R′)_(r)C(O)NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)C(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(6d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(6b), (CR′R′)_(r)OC(O)NR^(6a)(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6a)C(O)NR^(6a)(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d), (CR′R′)_(r)NR^(6f)C(O)O(CR′R′)_(r)R^(6b), (CR′R′)_(r)C(═NR^(6f))NR^(6a)R^(6a), (CR′R′)_(r)NHC(═NR^(6f))NR^(6f)R^(6f), (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(6b), (CR′R′)_(r)S(O)₂NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a), (CR′R′)_(r)NR^(6f)S(O)₂(CR′R′)_(r)R^(6b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(6e); alternatively, two R⁶ on adjacent atoms on R¹ may join to form a cyclic acetal; R^(6a), at each occurrence, is selected from H, methyl substituted with 0-1 R^(6g), C₂₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e); R^(6b), at each occurrence, is selected from H, C₁₋₆ alkyl substituted with 0-2 R^(6e), C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(6e); R^(6d), at each occurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(6e), C₃₋₈ alkynyl substituted with 0-2 R^(6e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e); R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R^(6f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(6g) is independently selected from —C(O)R^(6b), —C(O)OR^(6d), —C(O)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(7a)R^(7a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(7d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O) (CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)C(O) (CR′R′)_(r)R^(7b), (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)OC(O) (CR′R′)_(r)R^(7b), (CR′R′)_(r)OC(O)NR^(7a)(CR′R′)_(r)R^(7a), (CR′R′)_(r)NR^(7a)C(O)NR^(7a)(CR′R′)_(r)R^(7a), (CR′R′)_(r)NR^(7f)C(O)O(CR′R′)_(r)R^(7b), (CR′R′)_(r)C(═NR^(7f))NR^(7a)R^(7a), (CR′R′)_(r)NHC(═NR^(7f))NR^(7f)R^(7f), (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(7b), (CR′R′)_(r)S(O)₂NR^(7a)R^(7a), (CR′R′)_(r)NR^(7a)S(O)₂NR^(7a)R^(7a), (CR′R′)_(r)NR^(7f)S(O)₂(CR′R′)_(r)R^(7b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(7e); alternatively, two R⁷ on adjacent atoms on R² may join to form a cyclic acetal; R^(7a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(7g), C₂₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e); R^(7b), at each occurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(7e), C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(7e); R^(7d), at each occurrence, is selected from C₃₋₈ alkenyl substituted with 0-2 R^(7e), C₃₋₈ alkynyl substituted with 0-2 R^(7e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e); R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(7g) is independently selected from —C(O)R^(7b), —C(O)OR^(7d), —C(O)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R′, at each occurrence, is selected from H, C₁₋₆ alkyl substituted with R^(6e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(6e); R⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; R⁹ is selected from, H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, and (CH₂)—R¹; R¹⁰ and R^(10a) are independently selected from H, and C₁₋₄alkyl substituted with 0-1 R^(10b), alternatively, R¹⁰ and R^(10a) can join to form a C₃₋₆ cycloalkyl; R^(10b), at each occurrence, is independently selected from —OH, —SH, NR^(10c)R^(10c), —C(O)NR^(10c)R^(10c), and —NHC(O)R^(10c); R^(10c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹¹ is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(11d), (CHR)^(q)S(O)_(p)R^(11d), (CHR)_(r)C(O)R^(11b), (CHR)_(r)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)R^(11a), (CHR)_(r)C(O)NR^(11a)OR^(11d), (CHR)_(q)NR^(11a)C(O)R^(11b), (CHR)_(q)NR^(11a)C(O)OR^(11d), (CHR)_(q)OC(O)NR^(11a)R^(11a), (CHR)_(r)C(O)OR^(11d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a (CHR)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11a), at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11b), at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11d), at each occurrence, is independently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R¹¹e, and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e); R^(11e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl; R^(11f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² is selected from H, C₁₋₄ alkyl, (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(12d), (CHR)_(q)S(O)_(p)R^(12d), (CHR)_(r)C(O)R^(12b), (CHR)_(r)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)R^(12a), (CHR)_(r)C(O)NR^(12a)OR^(12d), (CHR)_(q)NR^(12a)C(O)R^(12b), (CHR)_(q)NR^(12a)C(O)OR^(12d), (CHR)_(q)OC(O)NR^(12a)R^(12a), (CHR)_(r)C(O)OR^(12d), a (CHR)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a (CHR)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12a), at each occurrence, is independently selected from H, C₁₋₄ alkyl, C₃₋₄ alkenyl, C₃₋₄ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-5 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12b), at each occurrence, is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12d), at each occurrence, is independently selected from H, methyl, —CF₃, C₂₋₄ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, a C₃₋₆ carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e); R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl; R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹³, at each occurrence, is independently selected from methyl, C₂₋₄ alkyl substituted with 0-1 R^(13b); R^(13b) is selected from —OH, —SH, —NR^(13c)R^(13c), —C(O)NR^(13c)R^(13c), and —NHC(O)R^(13c); R^(13c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; n is selected from 1 and 2; m is selected from 0 and 1; p, at each occurrence, is independently selected from 0, 1, and 2; q, at each occurrence, is independently selected from 1, 2, 3, and 4; r, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; s, at each occurrence, is independently selected from 0 and 1; and t, at each occurrence, is independently selected from 2, 3, and
 4. 3. The compound of claim 2, wherein: R¹⁰ and R^(10a) are H; m is 0; n is 1; and s is
 0. 4. The compound of claim 3, wherein: ring B is selected from

ring B being optionally substituted with 0-1 R⁵; and R¹¹ and R¹² are H.
 5. The compound of claim 4, wherein: R⁵, at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(5d), (CRR)_(r)SR^(5d), (CRR)_(r)NR^(5a)R^(5a), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)R^(5b), (CRR)_(r)C(O)NR^(5a)R^(5a), (CRR)_(r)NR^(5a)C(O)R^(5b), (CRR)_(r)NR^(5a)C(O)OR^(5d), (CRR)_(r)OC(O)NR^(5a)R^(5a), (CHR)_(r)NR^(5a)C(O)NR^(5a)R^(5a), CRR(CRR)_(r)NR^(5a)C(O)H, (CRR)_(r)C(O)OR^(5b), (CRR)_(r)OC(O)R^(5b), (CRR)_(r)S(O)_(p)R^(5b), (CRR)_(r)S(O)₂NR^(5a)R^(5a), (CRR)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl; R^(5a), at each occurrence, is independently selected from H, methyl, C₁₋₆ alkyl substituted with 0-2 R^(5e) wherein the alkyl is selected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, C₃ alkenyl substituted with 0-1 R^(5e), wherein the alkenyl is selected from allyl, C₃ alkynyl substituted with 0-1 R^(5e) wherein the alkynyl is selected from propynyl, and a (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with 0-5 R^(5e), wherein the carbocyclic residue is selected from cyclopropyl, and cyclobutyl; R_(5b), at each occurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(5e), wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, a (CH₂)_(r)—C₃₋₄ carbocyclic residue substituted with 0-2 R^(5e), wherein the carbocyclic residue is selected from cyclopropyl, and cyclobutyl; and R_(5d), at each occurrence, is selected from methyl, CF₃, C₂₋₆ alkyl substituted with 0-2 R^(5e), wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, and a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e).
 6. The compound of claim 5, wherein: R⁴ is selected from H, C₁₋₆ alkyl, C₃₋₈ alkenyl, C₃₋₈ alkynyl, (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b); R, at each occurrence, is independently selected from H, methyl, ethyl, propyl, allyl, propynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(6e); R⁵, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CH₂)_(r)OH, (CH₂)_(r)OR^(5d), (CH₂)_(r)NR^(5a)R^(5a), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(5b), (CH₂)_(r)C(O)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)OC(O)NR^(5a)R^(5a), (CH₂)_(r)NR^(5a)C(O)OR^(5d), (CH₂)_(r)NR^(5a)C(O)R^(5b), (CH₂)_(r)C(O)OR^(5b), (CH₂)_(r)OC(O)R^(5b), (CH₂)_(r)NR^(5a)S(O)₂R^(5b), and C₁₋₆ haloalkyl; R^(5a), at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, cyclopropyl, and cyclobutyl; and r, at each occurrence, is selected from 0, 1, and
 2. 7. The compound of claim 6, wherein: R¹ is selected from phenyl substituted with 0-2 R⁶, naphthyl substituted with 0-2R⁶, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R⁶ wherein the heteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl; R² is selected from phenyl substituted with 0-2 R⁷, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R⁷ wherein the heteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl; R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CRR)_(q)OH, (CRR)_(t)SH, (CRR)_(t)OR^(4d), (CRR)_(t)SR^(4d), (CRR)_(t)NR^(4a)R^(4a), (CRR)_(q)C(O)OH, (CRR)_(r)C(O)R^(4b), (CRR)_(r)C(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(t)OC(O)NR^(4a)R^(4a), (CRR)_(t)NR^(4a)C(O)OR^(4d), (CRR)_(t)NR^(4a)C(O)R^(4b), (CRR)_(r)C(O)OR^(4b), (CRR)_(t)OC(O)R^(4b), (CRR)_(r)S(O)_(p)R^(4b), (CRR)_(r)S(O)₂NR^(4a)R^(4a), (CRR)_(r)NR^(4a)S(O)₂R^(4b); R^(4a), at each occurrence, is independently selected from H, methyl substituted with 0-1 R^(4c), C₂₋₆ alkyl substituted with 0-3 R^(4e)wherein C₂₋₆ is selected from ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl and hexyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-4 R^(4e)wherein the carbocyclic residue is selected from cyclopropyl, cyclohexyl, and phenyl; R^(4b) is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; R^(4d) is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; R⁸ is selected from H, methyl, ethyl, propyl, i-propyl, and cyclopropyl; and R⁹ is selected from H, methyl, ethyl, propyl, i-propyl, and cyclopropyl, and CH₂—R¹.
 8. The compound of claim 7, wherein: R⁶, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)OH, (CRR)_(r)O(CRR)_(r)R^(6d), (CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(6d), (CRR)_(r)C(O)OH, (CRR)_(r)C(O)(CRR)_(r)R^(6b), (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)NR^(6f)C(O)(CRR)_(r)R^(6b), (CRR)_(r)C(O)O(CRR)_(r)R^(6d), (CRR)_(r)NR^(6a)C(O)NR^(6a)R^(6a), (CRR)_(r)NR^(6a)C(S)NR^(6a)R^(6a), (CRR)_(r)OC(O)(CRR)_(r)R^(6b), (CRR)_(r)S(O)_(p)(CRR)_(r)R^(6b), (CRR)_(r)S(O)₂NR^(6a)R^(6a), (CRR)_(r)NR^(6f)S(O)₂(CRR)_(r)R^(6b), (CRR)_(r)NR^(6f)S(O)₂ NR^(6a)R^(6a), C₁₋₆ haloalkyl, and (CRR)_(r)phenyl substituted with 0-3 R^(6e); R^(6a), at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl and phenyl; R^(6b), at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; R^(6d), at each occurrence, is selected from methyl, CF₃, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; R^(6e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl; R^(6f), at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s- butyl, t-butyl, pentyl, hexyl, (CRR)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN, (CRR)_(r)NR^(7a)R^(7a), (CRR)_(r)OH, (CRR)_(r)O(CH)_(r)R^(7d), (CRR)_(r)SH, (CRR)_(r)C(O)H, (CRR)_(r)S(CRR)_(r)R^(7d), (CRR)_(r)C(O)OH, (CRR)_(r)C(O) (CRR)_(r)R^(7b), (CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)NR^(7f)C(O)(CRR)_(r)R^(7b), (CRR)_(r)C(O)O(CRR)_(r)R^(7d), (CRR)_(r)OC(O)(CRR)_(r)R^(7b), (CRR)_(r)NR^(7a)C(O)NR^(7a)R^(7a), (CRR)_(r)NR^(7a)C(O)O(CRR)_(r)R^(7d), (CRR)_(r)S(O)_(p)(CRR)_(r)R^(7b), (CRR)_(r)S(O)₂NR^(7a)R^(7a), (CRR)_(r)NR^(7f)S(O)₂(CRR)_(r)R^(7b), C₁₋₆ haloalkyl, and (CRR)_(r)phenyl substituted with 0-3 R^(7e); R^(7a), at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH₂cyclopropyl, and benzyl; R^(7b), at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, CH₂-cyclopentyl, cyclohexyl, CH₂-cyclohexyl, CF₃, pyrrolidinyl, morpholinyl, and azetidinyl; R^(7d), at each occurrence, is selected from methyl, CF₃, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl; R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7f), at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; and r is 0 or
 1. 9. The compound of claim 8, wherein R⁷ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO₂, NR^(7a)R^(7a), NHC(O)NHR^(7a), NR^(7a)C(O)R^(7b), NR^(7a)C(O)OR^(7d), CF₃, OCF₃, C(O)R_(7b), NR^(7f)C(O)NR^(7a)R^(7a), NHS(O)₂R^(7b),


10. The compound of claim 9, wherein ring B is selected from

Z is —C(O)—; R^(1a) and R^(1b) are selected from H and methyl, or alternatively, R^(1a) and R^(1b) are taken together to form ═O; R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-3 R⁶ wherein the aryl group is selected from phenyl and naphthyl, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N and O, substituted with 0-3 R⁶ wherein the heteroaryl system is selected from furyl, indolyl, and benzotriazolyl; R² is phenyl substituted with 0-1 R⁷; R⁴ is selected from H, methyl, ethyl, propyl, i-propyl, butyl, I-butyl, t-butyl, pentyl, hexyl, and (CH₂)_(r) C(O)R^(4b); R⁶ is selected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I, NO₂, CN, O(CH₂)_(r)R^(6d), C(O)H, SR^(6d), NR^(6a)R^(6a), OC(O) R^(6b), S(O)_(p)R^(6b), (CHR′)_(r)S(O)₂NR^(6a)R^(6a), CF₃; R^(6a) is H methyl, or ethyl; R^(6b) is H or methyl; R^(6d) is methyl, phenyl, CF₃, and (CH₂)-phenyl; R⁹ is selected from H, methyl, and (CH₂)—R¹; and r is 0 or
 1. 11. The compound of claim 1, wherein the compound is selected from: N-[2-[[(cis) -2-[[1- (4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; N-[2-[[(1S, 2R) -2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; N-[2-[[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide; 2-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide; 2-{[1-Pyrrolidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Amino-N-({2-(cis)-(3-(4-methylthiophenyl)ureido]cyclohexylcarbamoyl}methyl)-5-trifluoromethyl benzamide; {2-[({2-(Cis)-[3-(4-methanesulfonylphenyl)ureido]cyclohexylcarbamoyl}methyl)carbamoyl]-4-trifluoromethylphenyl}carbamic acid tert-butyl ester; 2-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide; 2-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-methylthiobenzyl]amino)-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino)-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide; 2-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl)-5-(trifluoromethyl)benzamide; 3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; 2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide; 2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; 3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide; and N-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide.
 12. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 1. 13. A method for treating disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, said disorders being selected from osteoarthritis, aneurism, fever, cardiovascular effects, Crohn's disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 14. The method for treating disorders, of claim 13, wherein said disorders being selected from psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 15. The method for treating disorders, of claim 14, wherein said disorders being selected from alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 16. The method for treating disorders, of claim 15 wherein said disorders being selected from asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 17. A method for treating rheumatoid arthritis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim
 1. 18. A method for treating multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim
 1. 19. A method for treating atherosclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim
 1. 20. A method for treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim
 1. 